rs1799993

Positions:

• chr11-119087417-C-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000190.4(HMBS):​c.34-838C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.459 in 151,936 control chromosomes in the GnomAD database, including 17,599 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.46 (17597 hom., cov: 31)
  • Exomes 𝑓: 0.29 (2 hom.)
• Consequence: HMBS NM_000190.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.106

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.671 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HMBS	NM_000190.4	c.34-838C>A		intron_variant		ENST00000652429.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HMBS	ENST00000652429.1	c.34-838C>A		intron_variant			NM_000190.4	P3

Frequencies

GnomAD3 genomes AF: 0.459 AC: 69659 AN: 151786 Hom.: 17572 Cov.: 31

Gnomad AFR AF: 0.677

Gnomad AMI AF: 0.421

Gnomad AMR AF: 0.375

Gnomad ASJ AF: 0.406

Gnomad EAS AF: 0.184

Gnomad SAS AF: 0.348

Gnomad FIN AF: 0.284

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.404

Gnomad OTH AF: 0.461

GnomAD4 exome AF: 0.294 AC: 10 AN: 34 Hom.: 2 AF XY: 0.200 AC XY: 4 AN XY: 20

Gnomad4 AMR exome AF: 0.500

Gnomad4 EAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.308

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.459 AC: 69724 AN: 151902 Hom.: 17597 Cov.: 31 AF XY: 0.450 AC XY: 33364 AN XY: 74222

Gnomad4 AFR AF: 0.677

Gnomad4 AMR AF: 0.375

Gnomad4 ASJ AF: 0.406

Gnomad4 EAS AF: 0.184

Gnomad4 SAS AF: 0.348

Gnomad4 FIN AF: 0.284

Gnomad4 NFE AF: 0.404

Gnomad4 OTH AF: 0.462

Alfa AF: 0.418 Hom.: 14318

Bravo AF: 0.474

Asia WGS AF: 0.297 AC: 1031 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.95
DANN	Benign	0.67

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

Publications

LitVar

Other links and lift over

dbSNP: rs1799993; hg19: chr11-118958127;