11-119085172-CTTTTTTTTTTTTTTTTTTTTTT-CTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_000190.4(HMBS):c.33+128_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 0.040 (461 hom., cov: 0)
  • Exomes 𝑓: 0.015 (879 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 Benign. Variant got -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0672 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HMBS	NM_000190.4	c.33+128_33+135dup		intron_variant		ENST00000652429.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HMBS	ENST00000652429.1	c.33+128_33+135dup		intron_variant			NM_000190.4	P3

Frequencies

GnomAD3 genomes AF: 0.0402 AC: 2681 AN: 66682 Hom.: 461 Cov.: 0

Gnomad AFR AF: 0.0138

Gnomad AMI AF: 0.0870

Gnomad AMR AF: 0.0310

Gnomad ASJ AF: 0.0678

Gnomad EAS AF: 0.0793

Gnomad SAS AF: 0.0636

Gnomad FIN AF: 0.0279

Gnomad MID AF: 0.0750

Gnomad NFE AF: 0.0507

Gnomad OTH AF: 0.0341

GnomAD4 exome AF: 0.0147 AC: 10735 AN: 731206 Hom.: 879 Cov.: 0 AF XY: 0.0152 AC XY: 5491 AN XY: 361660

Gnomad4 AFR exome AF: 0.00343

Gnomad4 AMR exome AF: 0.0101

Gnomad4 ASJ exome AF: 0.0103

Gnomad4 EAS exome AF: 0.0282

Gnomad4 SAS exome AF: 0.0230

Gnomad4 FIN exome AF: 0.0256

Gnomad4 NFE exome AF: 0.0141

Gnomad4 OTH exome AF: 0.0149

GnomAD4 genome AF: 0.0402 AC: 2681 AN: 66718 Hom.: 461 Cov.: 0 AF XY: 0.0372 AC XY: 1098 AN XY: 29506

Gnomad4 AFR AF: 0.0138

Gnomad4 AMR AF: 0.0309

Gnomad4 ASJ AF: 0.0678

Gnomad4 EAS AF: 0.0792

Gnomad4 SAS AF: 0.0637

Gnomad4 FIN AF: 0.0279

Gnomad4 NFE AF: 0.0507

Gnomad4 OTH AF: 0.0339

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;