rs118204109

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 7P and 1B. PM1PP3_StrongPP5BS2_Supporting

The NM_000190.4(HMBS):c.601C>T(p.Arg201Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000168 in 1,550,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R201Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

HMBS
NM_000190.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 2.00

Publications

14 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: Likely_pathogenic. The variant received 6 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000190.4

PP3

MetaRNN computational evidence supports a deleterious effect, 0.993

PP5

Variant 11-119091515-C-T is Pathogenic according to our data. Variant chr11-119091515-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1462.We mark this variant Pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BS2

High AC in GnomAd4 at 6 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.601C>T	p.Arg201Trp	missense_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.601C>T	p.Arg201Trp	missense_variant	Exon 9 of 14		NM_000190.4	ENSP00000498786.1		P08397-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000256

AC:

AN:

155962

AF XY:

0.0000365

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000404

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000885

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000332

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000143

AC:

AN:

1397758

Hom.:

Cov.:

AF XY:

0.0000145

AC XY:

AN XY:

689526

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31562

American (AMR)

AF:

0.00

AC:

AN:

35704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25176

East Asian (EAS)

AF:

0.0000560

AC:

AN:

35736

South Asian (SAS)

AF:

0.0000126

AC:

AN:

79216

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49164

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.0000158

AC:

AN:

1077558

Other (OTH)

AF:

0.00

AC:

AN:

57946

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.440

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41470

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000829

Hom.:

Bravo

AF:

0.0000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Acute intermittent porphyria

Pathogenic:3

Dec 18, 2018

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The HMBS c.601C>T (p.Arg201Trp) missense variant has been reported in at least four studies in which it was found in a heterozygous state in at least 12 individuals with acute intermittent porphyria or hydroxymethylbilane synthase deficiency.(Lundin et al. 1994; Chen et al. 1994; Floderus et al. 2002; Cerbino et al. 2015). At least seven of these individuals were from one family in which the variant displayed segregation with disease (Lundin et al. 1994). Control data are unavailable for the p.Arg201Trp variant, which is reported at a frequency of 0.000027 in the total population of the Genome Aggregation Database. Functional studies conducted in E. coli indicate the variant form of the protein exhibited reduced enzymatic activity and stability compared to the wild type (Chen et al. 1994). Based on the collective evidence, the p.Arg201Trp variant is classified as pathogenic for hydroxymethylbilane synthase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Jan 01, 1994

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2_Supporting+PS3_Moderate+PS4_Moderate+PP4 -

not provided

Pathogenic:3

Dec 21, 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 tryptophan, which is neutral and slightly polar, at codon 201 of the HMBS protein (p.Arg201Trp). This variant is present in population databases (rs118204109, gnomAD 0.01%). This missense change has been observed in individual(s) with acute intermitent porphyria (PMID: 7962538, 8270256, 26075277). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1462). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt HMBS protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects HMBS function (PMID: 7962538, 11055586). For these reasons, this variant has been classified as Pathogenic. -

Nov 15, 2019

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 12372055, 7962538, 8270256, 26075277, 11055586) -

Jun 23, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP3, PP4, PM2, PS3 -

Encephalopathy, porphyria-related

Pathogenic:1

Watson Genetic Lab

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.53

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.99

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

Eigen

Uncertain

0.34

Eigen_PC

Benign

0.21

FATHMM_MKL

Pathogenic

0.97

M_CAP

Pathogenic

0.53

MetaRNN

Pathogenic

0.99

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.6

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

PhyloP100

2.0

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-7.7

.;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

0.90, 0.91, 0.88, 0.90, 0.86, 0.91

MutPred

0.92

.;Loss of MoRF binding (P = 0.0825);.;.;.;.;Loss of MoRF binding (P = 0.0825);.;.;.;.;.;.;

MVP

0.98

MPC

1.2

ClinPred

0.99

GERP RS

1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.96

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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rs118204109

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