11-119085172-CTTTTTTTTTTTTTTTTTTTTTT-CTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT

Variant summary

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

The NM_000190.4(HMBS):c.33+125_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 0.0059 (43 hom., cov: 0)
  • Exomes 𝑓: 0.0045 (176 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 eas. gnomad4 allele frequency = 0.0059 (394/66794) while in subpopulation EAS AF= 0.0171 (24/1404). AF 95% confidence interval is 0.0118. There are 43 homozygotes in gnomad4. There are 162 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 43 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HMBS	NM_000190.4	c.33+125_33+135dup		intron_variant		ENST00000652429.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HMBS	ENST00000652429.1	c.33+125_33+135dup		intron_variant			NM_000190.4	P3

Frequencies

GnomAD3 genomes AF: 0.00590 AC: 394 AN: 66758 Hom.: 43 Cov.: 0

Gnomad AFR AF: 0.00218

Gnomad AMI AF: 0.00866

Gnomad AMR AF: 0.00272

Gnomad ASJ AF: 0.00654

Gnomad EAS AF: 0.0171

Gnomad SAS AF: 0.00686

Gnomad FIN AF: 0.00178

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00787

Gnomad OTH AF: 0.00353

GnomAD4 exome AF: 0.00451 AC: 3300 AN: 732258 Hom.: 176 Cov.: 0 AF XY: 0.00469 AC XY: 1699 AN XY: 362166

Gnomad4 AFR exome AF: 0.00120

Gnomad4 AMR exome AF: 0.00313

Gnomad4 ASJ exome AF: 0.00328

Gnomad4 EAS exome AF: 0.00627

Gnomad4 SAS exome AF: 0.00739

Gnomad4 FIN exome AF: 0.00511

Gnomad4 NFE exome AF: 0.00441

Gnomad4 OTH exome AF: 0.00395

GnomAD4 genome AF: 0.00590 AC: 394 AN: 66794 Hom.: 43 Cov.: 0 AF XY: 0.00548 AC XY: 162 AN XY: 29536

Gnomad4 AFR AF: 0.00217

Gnomad4 AMR AF: 0.00271

Gnomad4 ASJ AF: 0.00654

Gnomad4 EAS AF: 0.0171

Gnomad4 SAS AF: 0.00688

Gnomad4 FIN AF: 0.00178

Gnomad4 NFE AF: 0.00787

Gnomad4 OTH AF: 0.00350

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;