11-119085172-CTTTTTTTTTTTTTTTTTTTTTT-CTTTTTTTTTTTTTTTT

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_000190.4(HMBS):c.33+130_33+135del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0188 in 790,702 control chromosomes in the GnomAD database, including 13 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0021 (2 hom., cov: 0)
  • Exomes 𝑓: 0.020 (11 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.

• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0587 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HMBS	NM_000190.4	c.33+130_33+135del		intron_variant		ENST00000652429.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HMBS	ENST00000652429.1	c.33+130_33+135del		intron_variant			NM_000190.4	P3

Frequencies

GnomAD3 genomes AF: 0.00208 AC: 139 AN: 66766 Hom.: 2 Cov.: 0

Gnomad AFR AF: 0.000544

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000418

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0200

Gnomad SAS AF: 0.0701

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000193

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0204 AC: 14734 AN: 723900 Hom.: 11 AF XY: 0.0207 AC XY: 7391 AN XY: 357690

Gnomad4 AFR exome AF: 0.0284

Gnomad4 AMR exome AF: 0.0205

Gnomad4 ASJ exome AF: 0.0165

Gnomad4 EAS exome AF: 0.0380

Gnomad4 SAS exome AF: 0.0350

Gnomad4 FIN exome AF: 0.0121

Gnomad4 NFE exome AF: 0.0188

Gnomad4 OTH exome AF: 0.0220

GnomAD4 genome AF: 0.00210 AC: 140 AN: 66802 Hom.: 2 Cov.: 0 AF XY: 0.00311 AC XY: 92 AN XY: 29536

Gnomad4 AFR AF: 0.000598

Gnomad4 AMR AF: 0.000417

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0199

Gnomad4 SAS AF: 0.0703

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000193

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;