11-119085172-CTTTTTTTTTTTTTTTTTTTTTT-CTTTTTTTTTTT

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+135del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0124 in 798,278 control chromosomes in the GnomAD database, including 28 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.010 (11 hom., cov: 0)
  • Exomes 𝑓: 0.013 (17 hom.)
• Consequence: HMBS NM_000190.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.83

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 = 0.01 (671/66818) while in subpopulation NFE AF= 0.0138 (501/36242). AF 95% confidence interval is 0.0128. There are 11 homozygotes in gnomad4. There are 272 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 11 SD gene

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0100 AC: 671 AN: 66782 Hom.: 11 Cov.: 0

Gnomad AFR AF: 0.00572

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00855

Gnomad ASJ AF: 0.000467

Gnomad EAS AF: 0.00214

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00533

Gnomad MID AF: 0.0250

Gnomad NFE AF: 0.0138

Gnomad OTH AF: 0.0141

GnomAD4 exome AF: 0.0127 AC: 9258 AN: 731460 Hom.: 17 AF XY: 0.0122 AC XY: 4427 AN XY: 361808

Gnomad4 AFR exome AF: 0.0450

Gnomad4 AMR exome AF: 0.0119

Gnomad4 ASJ exome AF: 0.00174

Gnomad4 EAS exome AF: 0.0109

Gnomad4 SAS exome AF: 0.00124

Gnomad4 FIN exome AF: 0.00484

Gnomad4 NFE exome AF: 0.0130

Gnomad4 OTH exome AF: 0.0137

GnomAD4 genome AF: 0.0100 AC: 671 AN: 66818 Hom.: 11 Cov.: 0 AF XY: 0.00921 AC XY: 272 AN XY: 29548

Gnomad4 AFR AF: 0.00571

Gnomad4 AMR AF: 0.00854

Gnomad4 ASJ AF: 0.000467

Gnomad4 EAS AF: 0.00214

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00533

Gnomad4 NFE AF: 0.0138

Gnomad4 OTH AF: 0.0140

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;