11-119085172-CTTTTTTTTTTTTTTTTTTTTTT-CTTTTTTTTTTTTTTTTTTTTTTTT

Variant summary

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

The NM_000190.4(HMBS):c.33+134_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 0.0012 (6 hom., cov: 0)
  • Exomes 𝑓: 0.0037 (96 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_exome allele frequency = 0.00374 (2733/731304) while in subpopulation EAS AF= 0.012 (93/7770). AF 95% confidence interval is 0.01. There are 96 homozygotes in gnomad4_exome. There are 1334 alleles in male gnomad4_exome subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HMBS	NM_000190.4	c.33+134_33+135dup		intron_variant		ENST00000652429.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HMBS	ENST00000652429.1	c.33+134_33+135dup		intron_variant			NM_000190.4	P3

Frequencies

GnomAD3 genomes AF: 0.00124 AC: 83 AN: 66768 Hom.: 6 Cov.: 0

Gnomad AFR AF: 0.00370

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000626

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000304

Gnomad OTH AF: 0.00117

GnomAD4 exome AF: 0.00374 AC: 2733 AN: 731304 Hom.: 96 Cov.: 0 AF XY: 0.00369 AC XY: 1334 AN XY: 361734

Gnomad4 AFR exome AF: 0.00294

Gnomad4 AMR exome AF: 0.00976

Gnomad4 ASJ exome AF: 0.00319

Gnomad4 EAS exome AF: 0.0120

Gnomad4 SAS exome AF: 0.00589

Gnomad4 FIN exome AF: 0.00841

Gnomad4 NFE exome AF: 0.00327

Gnomad4 OTH exome AF: 0.00396

GnomAD4 genome AF: 0.00124 AC: 83 AN: 66804 Hom.: 6 Cov.: 0 AF XY: 0.00129 AC XY: 38 AN XY: 29542

Gnomad4 AFR AF: 0.00370

Gnomad4 AMR AF: 0.000626

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000304

Gnomad4 OTH AF: 0.00117

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;