11-119085172-CTTTTTTTTTTTTTTTTTTTTTT-CTTTTTTTTTT

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BS1

The NM_000190.4(HMBS):c.33+124_33+135del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00458 in 798,458 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00097 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0049 (1 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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.00491 (3593/731650) while in subpopulation AFR AF= 0.0105 (192/18268). AF 95% confidence interval is 0.00929. There are 1 homozygotes in gnomad4_exome. There are 1789 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HMBS	NM_000190.4	c.33+124_33+135del		intron_variant		ENST00000652429.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HMBS	ENST00000652429.1	c.33+124_33+135del		intron_variant			NM_000190.4	P3

Frequencies

GnomAD3 genomes AF: 0.000973 AC: 65 AN: 66772 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000871

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00146

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00305

Gnomad FIN AF: 0.00178

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000966

Gnomad OTH AF: 0.00117

GnomAD4 exome AF: 0.00491 AC: 3593 AN: 731650 Hom.: 1 AF XY: 0.00494 AC XY: 1789 AN XY: 361880

Gnomad4 AFR exome AF: 0.0105

Gnomad4 AMR exome AF: 0.00399

Gnomad4 ASJ exome AF: 0.00464

Gnomad4 EAS exome AF: 0.00409

Gnomad4 SAS exome AF: 0.00252

Gnomad4 FIN exome AF: 0.00467

Gnomad4 NFE exome AF: 0.00495

Gnomad4 OTH exome AF: 0.00540

GnomAD4 genome AF: 0.000973 AC: 65 AN: 66808 Hom.: 0 Cov.: 0 AF XY: 0.00108 AC XY: 32 AN XY: 29540

Gnomad4 AFR AF: 0.000869

Gnomad4 AMR AF: 0.00146

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00306

Gnomad4 FIN AF: 0.00178

Gnomad4 NFE AF: 0.000966

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;