chr11-119085056-C-T

Position:

• chr11-119085056-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001425052.1(HMBS):​c.-120C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,320 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: HMBS NM_001425052.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.42

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19464234).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HMBS	NM_000190.4	c.23C>T	p.Ala8Val	missense_variant	1/14	ENST00000652429.1	NP_000181.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HMBS	ENST00000652429.1	c.23C>T	p.Ala8Val	missense_variant	1/14		NM_000190.4	ENSP00000498786.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461320 Hom.: 0 Cov.: 43 AF XY: 0.00000413 AC XY: 3 AN XY: 726986

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	.;T;T;.;T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.39	N
M_CAP	Pathogenic	0.41	D
MetaRNN	Benign	0.19	T;T;T;T;T
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Benign	0.90	.;L;.;L;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.19	.;N;N;N;N
REVEL	Uncertain	0.39
Sift	Benign	0.054	.;T;D;D;T
Sift4G	Benign	0.17	.;T;T;T;T
Polyphen		0.15, 0.39	.;B;.;.;B
Vest4		0.25, 0.24, 0.36
MutPred		0.26		Loss of helix (P = 0.0104);Loss of helix (P = 0.0104);Loss of helix (P = 0.0104);Loss of helix (P = 0.0104);Loss of helix (P = 0.0104);
MVP		0.71
MPC		0.68
ClinPred		0.88	D
GERP RS		3.9
Varity_R		0.086

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: chr11-118955766;