11-119085172-CTTTTTTTTTTTTTTTTTTTTTT-CTTTTTTTTTTTTTTTTTTTTTTTTTTT

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS1 BS2

The NM_000190.4(HMBS):c.33+131_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 0.031 (285 hom., cov: 0)
  • Exomes 𝑓: 0.021 (1092 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.

• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0309 (2059/66714) while in subpopulation NFE AF= 0.0397 (1435/36188). AF 95% confidence interval is 0.0379. There are 285 homozygotes in gnomad4. There are 821 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 285 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HMBS	NM_000190.4	c.33+131_33+135dup		intron_variant		ENST00000652429.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HMBS	ENST00000652429.1	c.33+131_33+135dup		intron_variant			NM_000190.4	P3

Frequencies

GnomAD3 genomes AF: 0.0309 AC: 2059 AN: 66678 Hom.: 285 Cov.: 0

Gnomad AFR AF: 0.0227

Gnomad AMI AF: 0.0217

Gnomad AMR AF: 0.0203

Gnomad ASJ AF: 0.0135

Gnomad EAS AF: 0.0292

Gnomad SAS AF: 0.00534

Gnomad FIN AF: 0.00357

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0397

Gnomad OTH AF: 0.0235

GnomAD4 exome AF: 0.0213 AC: 15561 AN: 729152 Hom.: 1092 Cov.: 0 AF XY: 0.0212 AC XY: 7635 AN XY: 360628

Gnomad4 AFR exome AF: 0.00670

Gnomad4 AMR exome AF: 0.0169

Gnomad4 ASJ exome AF: 0.0170

Gnomad4 EAS exome AF: 0.0427

Gnomad4 SAS exome AF: 0.0257

Gnomad4 FIN exome AF: 0.0259

Gnomad4 NFE exome AF: 0.0213

Gnomad4 OTH exome AF: 0.0197

GnomAD4 genome AF: 0.0309 AC: 2059 AN: 66714 Hom.: 285 Cov.: 0 AF XY: 0.0278 AC XY: 821 AN XY: 29494

Gnomad4 AFR AF: 0.0226

Gnomad4 AMR AF: 0.0203

Gnomad4 ASJ AF: 0.0135

Gnomad4 EAS AF: 0.0292

Gnomad4 SAS AF: 0.00536

Gnomad4 FIN AF: 0.00357

Gnomad4 NFE AF: 0.0397

Gnomad4 OTH AF: 0.0233

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;