11-119085172-CTTTTTTTTTTTTTTTTTTTTTT-CTTTTTTTTTTTTTTTTTTTTTTT

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS1 BS2

The NM_000190.4(HMBS):c.33+135dup 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 0.0039 (11 hom., cov: 0)
  • Exomes 𝑓: 0.0061 (34 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 Benign. Variant got -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00386 (258/66784) while in subpopulation AFR AF= 0.00565 (104/18394). AF 95% confidence interval is 0.00477. There are 11 homozygotes in gnomad4. There are 118 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 11 SD gene

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00387 AC: 258 AN: 66748 Hom.: 11 Cov.: 0

Gnomad AFR AF: 0.00566

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00418

Gnomad ASJ AF: 0.0117

Gnomad EAS AF: 0.000713

Gnomad SAS AF: 0.000762

Gnomad FIN AF: 0.000888

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00282

Gnomad OTH AF: 0.00469

GnomAD4 exome AF: 0.00605 AC: 4423 AN: 730766 Hom.: 34 Cov.: 0 AF XY: 0.00610 AC XY: 2204 AN XY: 361404

Gnomad4 AFR exome AF: 0.00278

Gnomad4 AMR exome AF: 0.0226

Gnomad4 ASJ exome AF: 0.00706

Gnomad4 EAS exome AF: 0.00758

Gnomad4 SAS exome AF: 0.00808

Gnomad4 FIN exome AF: 0.00914

Gnomad4 NFE exome AF: 0.00555

Gnomad4 OTH exome AF: 0.00632

GnomAD4 genome AF: 0.00386 AC: 258 AN: 66784 Hom.: 11 Cov.: 0 AF XY: 0.00400 AC XY: 118 AN XY: 29534

Gnomad4 AFR AF: 0.00565

Gnomad4 AMR AF: 0.00417

Gnomad4 ASJ AF: 0.0117

Gnomad4 EAS AF: 0.000712

Gnomad4 SAS AF: 0.000765

Gnomad4 FIN AF: 0.000888

Gnomad4 NFE AF: 0.00282

Gnomad4 OTH AF: 0.00466

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;