11-119091413-C-T

Position:

chr11-119091413-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_000190.4(HMBS):c.499C>T(p.Arg167Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000179 in 1,398,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as 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: not found (cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

HMBS
NM_000190.4 missense, splice_region

Scores

Splicing: ADA: 0.3266

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 2.50

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-119091414-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1446.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

PP5

Variant 11-119091413-C-T is Pathogenic according to our data. Variant chr11-119091413-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1456.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HMBS	NM_000190.4 linkuse as main transcript	c.499C>T	p.Arg167Trp	missense_variant, splice_region_variant	9/14	ENST00000652429.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HMBS	ENST00000652429.1 linkuse as main transcript	c.499C>T	p.Arg167Trp	missense_variant, splice_region_variant	9/14		NM_000190.4	P3	P08397-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000384

AC:

AN:

156320

Hom.:

AF XY:

0.0000243

AC XY:

AN XY:

82266

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000404

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000195

Gnomad NFE exome

AF:

0.0000331

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000179

AC:

AN:

1398000

Hom.:

Cov.:

AF XY:

0.0000145

AC XY:

AN XY:

689650

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000280

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000122

Gnomad4 NFE exome

AF:

0.0000130

Gnomad4 OTH exome

AF:

0.0000690

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000844

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000216

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Acute intermittent porphyria

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 24, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2004	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 21, 2019	Published functional studies demonstrate a damaging effect on enzyme kinetics, resulting in 1-5% of normal enzyme activity and leading to an accumulation of porphyrin precursors (Bustad et al., 2013; Solis et al., 2004; Chen et al., 2016).; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 11202057, 1577472, 15534187, 23815679, 12699244, 27539938, 11055586, 1301948, 2243128, 15643298, 15003823, 1496994) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 06, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 167 of the HMBS protein (p.Arg167Trp). This variant is present in population databases (rs118204101, gnomAD 0.02%). This missense change has been observed in individuals with acute intermittent porphyria (PMID: 1496994, 1577472, 15003823, 15534187, 15643298, 23815679). ClinVar contains an entry for this variant (Variation ID: 1456). 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: 1496994, 11055586, 23815679, 27539938). 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: 1496994, 1577472, 2243128, 7962538, 9199558, 12372055, 15003823, 15643298, 23815679). 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. -

Encephalopathy, porphyria-related

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

DANN

Pathogenic

1.0

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.95

M_CAP

Pathogenic

0.64

MetaRNN

Pathogenic

0.99

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

MetaSVM

Pathogenic

0.92

MutationTaster

Benign

1.0

A;A;A;A;A;A;A

PrimateAI

Pathogenic

0.80

REVEL

Pathogenic

0.94

Polyphen

1.0

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

Vest4

0.99, 0.99, 0.98, 0.97, 0.98, 0.99

MutPred

0.94

.;Loss of disorder (P = 0.005);.;.;.;.;Loss of disorder (P = 0.005);.;.;.;.;.;.;

MVP

0.99

MPC

0.75

ClinPred

1.0

GERP RS

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.33

dbscSNV1_RF

Benign

0.37

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over