11-119085034-A-G

Variant names:

• chr11-119085034-A-G
• rs118204118
• NM_000190.4:c.1A>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_000190.4(HMBS):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: HMBS NM_000190.4 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 2.64

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 1 pathogenic variants. Next in-frame start position is after 18 codons. Genomic position: 119088273. Lost 0.048 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMBS	NM_000190.4	c.1A>G	p.Met1?	start_lost	Exon 1 of 14	ENST00000652429.1	NP_000181.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMBS	ENST00000652429.1	c.1A>G	p.Met1?	start_lost	Exon 1 of 14		NM_000190.4	ENSP00000498786.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 42

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Porphyria, acute intermittent, nonerythroid variant Pathogenic:1

Nov 01, 1994

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Uncertain:1

Jul 06, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the HMBS mRNA. The next in-frame methionine is located at codon 18. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with clinical features of HMBS-related conditions (PMID: 7962538, 12406973). ClinVar contains an entry for this variant (Variation ID: 1484). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of the initiator codon affects HMBS function (PMID: 27539938). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	.;T;T;.;T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.2	D
PROVEAN	Benign	-0.96	N;N;N;N;N
REVEL	Pathogenic	0.70
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	.;D;D;T;T
Polyphen		0.92, 0.86	.;P;.;.;P
Vest4		0.87, 0.88, 0.93
MutPred		1.0		Loss of phosphorylation at S2 (P = 0.1125);Loss of phosphorylation at S2 (P = 0.1125);Loss of phosphorylation at S2 (P = 0.1125);Loss of phosphorylation at S2 (P = 0.1125);Loss of phosphorylation at S2 (P = 0.1125);
MVP		0.97
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.91

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

LitVar

Other links and lift over

dbSNP: rs118204118; hg19: chr11-118955744;