11-119085172-CTTTTTTTTTTTTTTTTTTTTTT-CTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT

Variant summary

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

The NM_000190.4(HMBS):c.33+126_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 0.0071 (78 hom., cov: 0)
  • Exomes 𝑓: 0.0064 (268 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 eas. gnomad4 allele frequency = 0.00707 (472/66788) while in subpopulation EAS AF= 0.0321 (45/1402). AF 95% confidence interval is 0.0247. There are 78 homozygotes in gnomad4. There are 183 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 78 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HMBS	NM_000190.4	c.33+126_33+135dup		intron_variant		ENST00000652429.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HMBS	ENST00000652429.1	c.33+126_33+135dup		intron_variant			NM_000190.4	P3

Frequencies

GnomAD3 genomes AF: 0.00707 AC: 472 AN: 66752 Hom.: 78 Cov.: 0

Gnomad AFR AF: 0.00218

Gnomad AMI AF: 0.00435

Gnomad AMR AF: 0.00480

Gnomad ASJ AF: 0.00561

Gnomad EAS AF: 0.0321

Gnomad SAS AF: 0.0122

Gnomad FIN AF: 0.00624

Gnomad MID AF: 0.0375

Gnomad NFE AF: 0.00880

Gnomad OTH AF: 0.00587

GnomAD4 exome AF: 0.00640 AC: 4687 AN: 732004 Hom.: 268 Cov.: 0 AF XY: 0.00653 AC XY: 2363 AN XY: 362054

Gnomad4 AFR exome AF: 0.00190

Gnomad4 AMR exome AF: 0.00559

Gnomad4 ASJ exome AF: 0.00482

Gnomad4 EAS exome AF: 0.0136

Gnomad4 SAS exome AF: 0.00955

Gnomad4 FIN exome AF: 0.00678

Gnomad4 NFE exome AF: 0.00620

Gnomad4 OTH exome AF: 0.00678

GnomAD4 genome AF: 0.00707 AC: 472 AN: 66788 Hom.: 78 Cov.: 0 AF XY: 0.00620 AC XY: 183 AN XY: 29532

Gnomad4 AFR AF: 0.00217

Gnomad4 AMR AF: 0.00480

Gnomad4 ASJ AF: 0.00561

Gnomad4 EAS AF: 0.0321

Gnomad4 SAS AF: 0.0122

Gnomad4 FIN AF: 0.00624

Gnomad4 NFE AF: 0.00881

Gnomad4 OTH AF: 0.00583

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;