rs118204115

Variant names:

• chr11-119092518-C-A
• rs118204115
• NM_000190.4:c.766C>A

Your query was ambiguous. Multiple possible variants found:

• chr11-119092518-C-A
• chr11-119092518-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_000190.4(HMBS):​c.766C>A​(p.His256Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H256Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HMBS NM_000190.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.90
• Publications: 5 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000190.4
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-119092518-C-A is Pathogenic according to our data. Variant chr11-119092518-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 1474.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMBS	NM_000190.4	c.766C>A	p.His256Asn	missense_variant	Exon 11 of 14	ENST00000652429.1	NP_000181.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMBS	ENST00000652429.1	c.766C>A	p.His256Asn	missense_variant	Exon 11 of 14		NM_000190.4	ENSP00000498786.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Acute intermittent porphyria Pathogenic:1

Dec 01, 1993

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.66	.;D;.;T;.;.;.;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.71	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	.;M;.;.;.;.;.;.
PhyloP100		2.9
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.21	.;N;N;N;.;.;N;.
REVEL	Uncertain	0.57
Sift	Benign	0.47	.;T;T;T;.;.;T;.
Sift4G	Benign	0.37	.;T;T;T;.;.;T;.
Polyphen		0.55, 0.49	.;P;.;P;.;.;.;.
Vest4		0.57, 0.57, 0.58
MutPred		0.82		.;Gain of methylation at R255 (P = 0.2814);.;.;.;.;.;.;
MVP		0.78
MPC		0.45
ClinPred		0.72	D
GERP RS		5.2
Varity_R		0.40
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs118204115; hg19: chr11-118963228;