11-119085172-CTTTTTTTTTTTTTTTTTTTTTT-CTTTTTTTTTTTTTTTTTTTTTTTTT

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS1

The NM_000190.4(HMBS):c.33+133_33+135dup variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0056 (213 hom.)
• Consequence: HMBS NM_000190.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.497

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 Likely_benign. Variant got -4 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.00559 (4089/731348) while in subpopulation EAS AF= 0.0146 (113/7752). AF 95% confidence interval is 0.0124. There are 213 homozygotes in gnomad4_exome. There are 2074 alleles in male gnomad4_exome subpopulation. Median coverage is 0. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HMBS	NM_000190.4	c.33+133_33+135dup		intron_variant		ENST00000652429.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HMBS	ENST00000652429.1	c.33+133_33+135dup		intron_variant			NM_000190.4	P3

Frequencies

GnomAD3 genomes AF: 0.000225 AC: 15 AN: 66768 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000544

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000762

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000110

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00559 AC: 4089 AN: 731348 Hom.: 213 Cov.: 0 AF XY: 0.00573 AC XY: 2074 AN XY: 361712

Gnomad4 AFR exome AF: 0.00229

Gnomad4 AMR exome AF: 0.00865

Gnomad4 ASJ exome AF: 0.00492

Gnomad4 EAS exome AF: 0.0146

Gnomad4 SAS exome AF: 0.00793

Gnomad4 FIN exome AF: 0.00991

Gnomad4 NFE exome AF: 0.00525

Gnomad4 OTH exome AF: 0.00544

GnomAD4 genome AF: 0.000225 AC: 15 AN: 66804 Hom.: 0 Cov.: 0 AF XY: 0.000372 AC XY: 11 AN XY: 29540

Gnomad4 AFR AF: 0.000543

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000765

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000110

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs549270240; hg19: chr11-118955882;