11-119085172-CTTTTTTTTTTTTTTTTTTTTTT-CTTTTTTTTTTTTTTTTTTTTT

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS1

The NM_000190.4(HMBS):c.33+135del variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0035 (0 hom., cov: 0)
  • Exomes 𝑓: 0.014 (30 hom.)
• Consequence: HMBS NM_000190.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.497

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 -4 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0035 (234/66768) while in subpopulation AFR AF= 0.00963 (177/18386). AF 95% confidence interval is 0.00847. There are 0 homozygotes in gnomad4. There are 114 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00346 AC: 231 AN: 66732 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00948

Gnomad AMI AF: 0.00217

Gnomad AMR AF: 0.00376

Gnomad ASJ AF: 0.00187

Gnomad EAS AF: 0.00143

Gnomad SAS AF: 0.000762

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000801

Gnomad OTH AF: 0.00235

GnomAD4 exome AF: 0.0145 AC: 10523 AN: 725758 Hom.: 30 Cov.: 0 AF XY: 0.0145 AC XY: 5186 AN XY: 358840

Gnomad4 AFR exome AF: 0.0105

Gnomad4 AMR exome AF: 0.0285

Gnomad4 ASJ exome AF: 0.0101

Gnomad4 EAS exome AF: 0.00721

Gnomad4 SAS exome AF: 0.00994

Gnomad4 FIN exome AF: 0.0124

Gnomad4 NFE exome AF: 0.0150

Gnomad4 OTH exome AF: 0.0140

GnomAD4 genome AF: 0.00350 AC: 234 AN: 66768 Hom.: 0 Cov.: 0 AF XY: 0.00386 AC XY: 114 AN XY: 29522

Gnomad4 AFR AF: 0.00963

Gnomad4 AMR AF: 0.00375

Gnomad4 ASJ AF: 0.00187

Gnomad4 EAS AF: 0.00143

Gnomad4 SAS AF: 0.000765

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000801

Gnomad4 OTH AF: 0.00233

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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;