NM_000190.4:c.606G>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000190.4(HMBS):c.606G>T(p.Val202Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.266 in 1,546,376 control chromosomes in the GnomAD database, including 56,567 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.24 ( 4502 hom., cov: 32)

Exomes 𝑓: 0.27 ( 52065 hom. )

Consequence

HMBS
NM_000190.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.11

Publications

18 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: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant 11-119091520-G-T is Benign according to our data. Variant chr11-119091520-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255485.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.11 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.279 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMBS	NM_000190.4 link	c.606G>T	p.Val202Val	synonymous_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.606G>T	p.Val202Val	synonymous_variant	Exon 9 of 14		NM_000190.4	ENSP00000498786.1		P08397-1

Frequencies

GnomAD3 genomes

AF:

0.235

AC:

35815

AN:

152088

Hom.:

4499

Cov.:

show subpopulations

Gnomad AFR

AF:

0.166

Gnomad AMI

AF:

0.313

Gnomad AMR

AF:

0.201

Gnomad ASJ

AF:

0.342

Gnomad EAS

AF:

0.171

Gnomad SAS

AF:

0.192

Gnomad FIN

AF:

0.262

Gnomad MID

AF:

0.244

Gnomad NFE

AF:

0.282

Gnomad OTH

AF:

0.247

GnomAD2 exomes

AF:

0.235

AC:

36676

AN:

155800

AF XY:

0.238

show subpopulations

Gnomad AFR exome

AF:

0.165

Gnomad AMR exome

AF:

0.155

Gnomad ASJ exome

AF:

0.348

Gnomad EAS exome

AF:

0.166

Gnomad FIN exome

AF:

0.260

Gnomad NFE exome

AF:

0.281

Gnomad OTH exome

AF:

0.260

GnomAD4 exome

AF:

0.269

AC:

375557

AN:

1394170

Hom.:

52065

Cov.:

AF XY:

0.268

AC XY:

184678

AN XY:

688072

show subpopulations

African (AFR)

AF:

0.163

AC:

5135

AN:

31484

American (AMR)

AF:

0.160

AC:

5720

AN:

35700

Ashkenazi Jewish (ASJ)

AF:

0.349

AC:

8782

AN:

25142

East Asian (EAS)

AF:

0.159

AC:

5664

AN:

35688

South Asian (SAS)

AF:

0.200

AC:

15807

AN:

79150

European-Finnish (FIN)

AF:

0.251

AC:

12332

AN:

49136

Middle Eastern (MID)

AF:

0.276

AC:

1571

AN:

5686

European-Non Finnish (NFE)

AF:

0.284

AC:

305246

AN:

1074374

Other (OTH)

AF:

0.265

AC:

15300

AN:

57810

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

13553

27106

40659

54212

67765

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10204

20408

30612

40816

51020

<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:

0.235

AC:

35821

AN:

152206

Hom.:

4502

Cov.:

AF XY:

0.234

AC XY:

17419

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.166

AC:

6888

AN:

41548

American (AMR)

AF:

0.201

AC:

3072

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.342

AC:

1187

AN:

3468

East Asian (EAS)

AF:

0.170

AC:

882

AN:

5178

South Asian (SAS)

AF:

0.192

AC:

928

AN:

4822

European-Finnish (FIN)

AF:

0.262

AC:

2778

AN:

10596

Middle Eastern (MID)

AF:

0.235

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.282

AC:

19204

AN:

67988

Other (OTH)

AF:

0.250

AC:

528

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1423

2846

4269

5692

7115

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

380

760

1140

1520

1900

<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:

0.258

Hom.:

10000

Bravo

AF:

0.228

Asia WGS

AF:

0.187

AC:

654

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Jul 06, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Acute intermittent porphyria

Benign:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Congenital disorder of glycosylation

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

7.1

(source)

DANN

Benign

0.81

PhyloP100

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=99/1

polymorphism (auto)

(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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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