rs118204105

Variant names:

• chr11-119088647-C-A
• rs118204105
• NM_000190.4:c.100C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000190.4(HMBS):​c.100C>A​(p.Gln34Lys) variant causes a missense change. 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 (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HMBS NM_000190.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.97
• Publications: 6 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000190.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 11-119088647-C-A is Pathogenic according to our data. Variant chr11-119088647-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1455.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.100C>A	p.Gln34Lys	missense_variant	Exon 3 of 14	ENST00000652429.1	NP_000181.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMBS	ENST00000652429.1	c.100C>A	p.Gln34Lys	missense_variant	Exon 3 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

Sep 01, 1992

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	30
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	1.0	.;D;.;.;D;.;.;D;.;.;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	4.5	.;H;.;.;.;.;H;.;.;.;.;.;.
PhyloP100		7.0
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.7	.;D;D;D;D;.;D;D;.;D;D;D;.
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	.;D;D;D;D;.;D;D;.;D;D;D;.
Sift4G	Pathogenic	0.0	.;D;D;D;D;.;D;D;.;D;D;D;.
Polyphen		1.0, 1.0	.;D;.;.;.;.;.;D;.;.;.;.;.
Vest4		0.99, 1.0, 0.96, 0.98, 0.97, 0.99
MutPred		0.99		Gain of catalytic residue at Q34 (P = 0.0293);Gain of catalytic residue at Q34 (P = 0.0293);.;.;Gain of catalytic residue at Q34 (P = 0.0293);.;Gain of catalytic residue at Q34 (P = 0.0293);.;.;.;.;.;.;
MVP		0.98
MPC		1.1
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.99
Mutation Taster		=2/98	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: rs118204105; hg19: chr11-118959357;