11-119085172-CTTTTTTTTTTTTTTTTTTTTTT-CTTTTTTT

Position:

• chr11-119085172-CTTTTTTTTTTTTTTTTTTTTTT-CTTTTTTT

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000190.4(HMBS):​c.33+121_33+135del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00138 in 798,578 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0015 (0 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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HMBS	NM_000190.4	c.33+121_33+135del		intron_variant		ENST00000652429.1	NP_000181.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HMBS	ENST00000652429.1	c.33+121_33+135del		intron_variant			NM_000190.4	ENSP00000498786	P3

Frequencies

GnomAD3 genomes AF: 0.000180 AC: 12 AN: 66770 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000163

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00143

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.000888

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000552

Gnomad OTH AF: 0.00117

GnomAD4 exome AF: 0.00149 AC: 1087 AN: 731772 Hom.: 0 AF XY: 0.00165 AC XY: 599 AN XY: 361962

Gnomad4 AFR exome AF: 0.000926

Gnomad4 AMR exome AF: 0.00102

Gnomad4 ASJ exome AF: 0.00493

Gnomad4 EAS exome AF: 0.000639

Gnomad4 SAS exome AF: 0.00216

Gnomad4 FIN exome AF: 0.00503

Gnomad4 NFE exome AF: 0.00129

Gnomad4 OTH exome AF: 0.00232

GnomAD4 genome AF: 0.000210 AC: 14 AN: 66806 Hom.: 0 Cov.: 0 AF XY: 0.000305 AC XY: 9 AN XY: 29540

Gnomad4 AFR AF: 0.000272

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00142

Gnomad4 SAS AF: 0.00229

Gnomad4 FIN AF: 0.000888

Gnomad4 NFE AF: 0.0000552

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;