11-119088298-G-T

Position:

• chr11-119088298-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_000190.4(HMBS):​c.77G>T​(p.Arg26Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HMBS NM_000190.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.97

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a mutagenesis_site Loss of hydroxymethylbilane synthase activity. (size 0) in uniprot entity HEM3_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 11-119088298-G-T is Pathogenic according to our data. Variant chr11-119088298-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 665873.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HMBS	NM_000190.4	c.77G>T	p.Arg26Leu	missense_variant	2/14	ENST00000652429.1	NP_000181.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HMBS	ENST00000652429.1	c.77G>T	p.Arg26Leu	missense_variant	2/14		NM_000190.4	ENSP00000498786.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 06, 2022

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg26 amino acid residue in HMBS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7757070, 8401516, 18627369, 24997713, 26095755, 26582343). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects HMBS function (PMID: 19656452). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 665873). This missense change has been observed in individual(s) with acute intermittent porphyria (PMID: 19656452; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 26 of the HMBS protein (p.Arg26Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	1.0	.;D;.;.;D;.;.;.;.;.;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	4.5	.;H;.;.;.;.;H;.;.;.;.;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-6.2	.;D;D;D;D;.;D;.;D;D;D;.
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	.;D;D;D;D;.;D;.;D;D;D;.
Sift4G	Pathogenic	0.0	.;D;D;D;D;.;D;.;D;D;D;.
Polyphen		1.0	.;D;.;.;.;.;.;.;.;.;.;.
Vest4		0.94, 0.94, 0.92, 0.92, 0.94
MutPred		0.99		Loss of disorder (P = 0.039);Loss of disorder (P = 0.039);.;.;Loss of disorder (P = 0.039);.;Loss of disorder (P = 0.039);.;.;.;.;.;
MVP		0.98
MPC		1.2
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.2
Varity_R		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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

Other links and lift over

dbSNP: rs118204103; hg19: chr11-118959008;