11-119085172-CTTTTTTTTTTTTTTTTTTTTTT-CTTTTT

Variant summary

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

The NM_000190.4(HMBS):c.33+119_33+135del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000124 in 799,448 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 0.000030 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00013 (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 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	UniProt
HMBS	NM_000190.4	c.33+119_33+135del		intron_variant		ENST00000652429.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HMBS	ENST00000652429.1	c.33+119_33+135del		intron_variant			NM_000190.4	P3

Frequencies

GnomAD3 genomes AF: 0.0000449 AC: 3 AN: 66768 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000544

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000713

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000276

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000132 AC: 97 AN: 732644 Hom.: 1 AF XY: 0.000124 AC XY: 45 AN XY: 362374

Gnomad4 AFR exome AF: 0.000381

Gnomad4 AMR exome AF: 0.000169

Gnomad4 ASJ exome AF: 0.000675

Gnomad4 EAS exome AF: 0.000256

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000440

Gnomad4 NFE exome AF: 0.000116

Gnomad4 OTH exome AF: 0.000181

GnomAD4 genome AF: 0.0000299 AC: 2 AN: 66804 Hom.: 0 Cov.: 0 AF XY: 0.0000339 AC XY: 1 AN XY: 29540

Gnomad4 AFR AF: 0.0000543

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000712

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

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;