rs118204116

Positions:

• chr11-119092159-G-A
• chr11-119092159-G-C

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.647G>A​(p.Gly216Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,756 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HMBS NM_000190.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.77

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 turn (size 3) in uniprot entity HEM3_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000190.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 11-119092159-G-A is Pathogenic according to our data. Variant chr11-119092159-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1478.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.647G>A	p.Gly216Asp	missense_variant	10/14	ENST00000652429.1	NP_000181.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HMBS	ENST00000652429.1	c.647G>A	p.Gly216Asp	missense_variant	10/14		NM_000190.4	ENSP00000498786.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461756 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727192

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Acute intermittent porphyria Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 1997

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 01, 2022

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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: 1478). This missense change has been observed in individuals with clinical features of acute intermittent porphyria (PMID: 9225970, 12372055, 31044425; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 216 of the HMBS protein (p.Gly216Asp). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	.;D;.;.;D;.;.;.;.;.;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	4.3	.;H;.;.;.;.;H;.;.;.;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-6.1	.;D;D;D;D;.;D;.;.;D;.
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	.;D;D;D;D;.;D;.;.;D;.
Sift4G	Uncertain	0.0040	.;D;D;D;D;.;D;.;.;D;.
Polyphen		0.98, 0.99	.;D;D;.;.;.;.;.;D;D;D
Vest4		0.98, 0.99, 0.94, 0.95, 0.98
MutPred		0.98		.;Loss of phosphorylation at Y213 (P = 0.1626);.;.;.;.;Loss of phosphorylation at Y213 (P = 0.1626);.;.;.;.;
MVP		0.98
MPC		1.2
ClinPred		1.0	D
GERP RS		4.4
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.1
Varity_R		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs118204116; hg19: chr11-118962869;