rs118204095

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 13P and 1B. PM1PM5PP3PP5_Very_StrongBS2_Supporting

The NM_000190.4(HMBS):c.500G>A(p.Arg167Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000703 in 1,550,946 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 15/25 in silico tools predict a damaging outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R167L) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000071 ( 0 hom. )

Consequence

HMBS
NM_000190.4 missense, splice_region

Scores

Splicing: ADA: 0.9801

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9U:1O:1

Conservation

PhyloP100: 9.93

Publications

36 publications found

Variant links:

Genes affected

HMBS (HGNC:4982): (hydroxymethylbilane synthase) This gene encodes a member of the hydroxymethylbilane synthase superfamily. The encoded protein is the third enzyme of the heme biosynthetic pathway and catalyzes the head to tail condensation of four porphobilinogen molecules into the linear hydroxymethylbilane. Mutations in this gene are associated with the autosomal dominant disease acute intermittent porphyria. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

HMBS Gene-Disease associations (from GenCC):

acute intermittent porphyria
Inheritance: SD, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet

HMBS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_000190.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-119091414-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1457.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 11-119091414-G-A is Pathogenic according to our data. Variant chr11-119091414-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1446.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 9 SD,AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMBS	NM_000190.4 link	c.500G>A	p.Arg167Gln	missense_variant, splice_region_variant	Exon 9 of 14	ENST00000652429.1	NP_000181.2	P08397-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMBS	ENST00000652429.1 link	c.500G>A	p.Arg167Gln	missense_variant, splice_region_variant	Exon 9 of 14		NM_000190.4	ENSP00000498786.1		P08397-1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000448

AC:

AN:

156322

AF XY:

0.0000243

show subpopulations

Gnomad AFR exome

AF:

0.000114

Gnomad AMR exome

AF:

0.0000404

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000662

Gnomad OTH exome

AF:

0.000227

GnomAD4 exome

AF:

0.0000715

AC:

100

AN:

1398710

Hom.:

Cov.:

AF XY:

0.0000754

AC XY:

AN XY:

689936

show subpopulations

African (AFR)

AF:

0.000127

AC:

AN:

31580

American (AMR)

AF:

0.0000560

AC:

AN:

35702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25180

East Asian (EAS)

AF:

0.0000280

AC:

AN:

35736

South Asian (SAS)

AF:

0.00

AC:

AN:

79218

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49260

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5692

European-Non Finnish (NFE)

AF:

0.0000853

AC:

AN:

1078394

Other (OTH)

AF:

0.0000173

AC:

AN:

57948

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41468

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5206

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000122

Hom.:

Bravo

AF:

0.0000756

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000855

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9Uncertain:1Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Acute intermittent porphyria

Pathogenic:4Uncertain:1Other:1

Feb 07, 2018

CENTOGENE GmbH and LLC - Guiding Precision Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

GenomeConnect - Invitae Patient Insights Network

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant interpreted as Pathogenic and reported on 03-26-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Sep 13, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: HMBS c.500G>A (p.Arg167Gln) results in a conservative amino acid change located in the N-terminal domain (IPR022417) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. In addition, this variant disrupts the second nucleotide of exon 9, and therefore can affect splicing. Several computational tools predict a significant impact on normal splicing: Two predict the variant weakens a 3' acceptor site. Two predict the variant creates a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.5e-05 in 156322 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.500G>A has been reported in the literature in multiple individuals affected with Acute Intermittent Porphyria (e.g., Delfau_1990, Chen_1994, vonBrasch_2004, Floderus_2002). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function, finding that the variant results in <10% of specific activity relative to wild type (e.g, Delfau_1990, Gill_2009). The following publications have been ascertained in the context of this evaluation (PMID: 7962538, 2243128, 12372055, 19207107, 15003823). Three submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Mount Sinai Diagnostic Laboratory, Icahn School of Medicine at Mount Sinai

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Nov 01, 2004

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Pathogenic:3

Oct 07, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP3, PM2, PM5, PS3 -

Dec 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 167 of the HMBS protein (p.Arg167Gln). This variant is present in population databases (rs118204095, gnomAD 0.01%). This missense change has been observed in individuals with autosomal dominant acute intermittent porphyria (PMID: 2243128, 7962538, 9199558, 12372055, 15003823). ClinVar contains an entry for this variant (Variation ID: 1446). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects HMBS function (PMID: 2243128, 12773194, 27539938). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Arg167 amino acid residue in HMBS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7962538, 11055586, 12372055, 15003823, 15643298, 23815679, 27539938). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Jun 13, 2024

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported in the compound heterozygous state with another HMBS variant in individuals from 2 families with spasticity, ataxia, neuropathy, and abnormal head imaging (PMID: 1577472, 27558376); Published functional studies demonstrate dramatic reduction in enzymatic activity to approximately 1% of wild type levels (PMID: 27539938, 2243128); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis supports that this missense variant has a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 19207107, 25637381, 2243128, 27558376, 29360981, 15534187, 32197664, 12773194, 12699244, 30615115, 7962538, 15003823, 9199558, 26075277, 12372055, 25016127, 34791078, 35327450, 34308104, 34089223, 27539938, 31153822, 1577472) -

Leukoencephalopathy, porphyria-related

Pathogenic:1

Nov 01, 2004

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Encephalopathy, porphyria-related

Pathogenic:1

Nov 01, 2004

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.61

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

1.0

.;D;.;.;D;.;.;D;.;.;.;.;.

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Pathogenic

0.99

M_CAP

Pathogenic

0.57

MetaRNN

Pathogenic

0.91

D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.90

MutationAssessor

Pathogenic

4.5

.;H;.;.;.;.;H;.;.;.;.;.;.

PhyloP100

9.9

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-3.9

.;D;D;D;D;.;D;D;.;D;D;D;.

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

.;D;D;D;D;.;D;D;.;D;D;D;.

Sift4G

Pathogenic

0.0

.;D;D;D;D;.;D;D;.;D;D;D;.

Polyphen

1.0

.;D;D;.;.;.;.;D;.;D;.;D;D

Vest4

0.98, 0.98, 0.97, 0.96, 0.97, 0.98

MVP

0.98

MPC

1.2

ClinPred

1.0

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.97

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

dbscSNV1_RF

Pathogenic

0.74

SpliceAI score (max)

0.80

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.80

Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over