11-119089084-G-C

Variant names:

• chr11-119089084-G-C
• NM_000190.4:c.163G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000190.4(HMBS):​c.163G>C​(p.Ala55Pro) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,506 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: HMBS NM_000190.4 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.94

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 2 ACMG points.

• 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.163G>C	p.Ala55Pro	missense_variant, splice_region_variant	Exon 4 of 14	ENST00000652429.1	NP_000181.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMBS	ENST00000652429.1	c.163G>C	p.Ala55Pro	missense_variant, splice_region_variant	Exon 4 of 14		NM_000190.4	ENSP00000498786.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459506 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726248

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;.;.;T;.;.;D;.;.;.;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.23	D
MetaRNN	Uncertain	0.70	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	0.23	N;.;.;.;.;N;.;.;.;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-2.0	N;N;N;N;.;N;N;N;N;N;.
REVEL	Pathogenic	0.74
Sift	Benign	0.086	T;T;T;T;.;T;T;T;T;T;.
Sift4G	Benign	0.19	T;T;T;T;.;T;T;T;T;T;.
Polyphen		1.0	D;.;.;.;.;.;D;.;.;.;.
Vest4		0.74
MutPred		0.65		Loss of stability (P = 0.0851);.;.;Loss of stability (P = 0.0851);.;Loss of stability (P = 0.0851);.;.;.;.;.;
MVP		0.86
MPC		0.64
ClinPred		0.86	D
GERP RS		6.2
Varity_R		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-118959794;