11-119085172-CTTTTTTTTTTTTTTTTTTTTTT-CTTTTTTTTTTTT

Position:

• chr11-119085172-CTTTTTTTTTTTTTTTTTTTTTT-CTTTTTTTTTTTT

Variant summary

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

The NM_000190.4(HMBS):​c.33+126_33+135del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0135 in 798,528 control chromosomes in the GnomAD database, including 470 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.075 (442 hom., cov: 0)
  • Exomes 𝑓: 0.0079 (28 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 (AFR) allele frequency at 95% confidence interval = 0.242 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HMBS	NM_000190.4	c.33+126_33+135del		intron_variant		ENST00000652429.1	NP_000181.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HMBS	ENST00000652429.1	c.33+126_33+135del		intron_variant			NM_000190.4	ENSP00000498786	P3

Frequencies

GnomAD3 genomes AF: 0.0754 AC: 5044 AN: 66884 Hom.: 440 Cov.: 0

Gnomad AFR AF: 0.248

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0527

Gnomad ASJ AF: 0.00187

Gnomad EAS AF: 0.00783

Gnomad SAS AF: 0.00229

Gnomad FIN AF: 0.000888

Gnomad MID AF: 0.0125

Gnomad NFE AF: 0.00386

Gnomad OTH AF: 0.0550

GnomAD4 exome AF: 0.00787 AC: 5757 AN: 731606 Hom.: 28 AF XY: 0.00732 AC XY: 2650 AN XY: 361880

Gnomad4 AFR exome AF: 0.158

Gnomad4 AMR exome AF: 0.0148

Gnomad4 ASJ exome AF: 0.00348

Gnomad4 EAS exome AF: 0.0218

Gnomad4 SAS exome AF: 0.00190

Gnomad4 FIN exome AF: 0.00123

Gnomad4 NFE exome AF: 0.00328

Gnomad4 OTH exome AF: 0.0153

GnomAD4 genome AF: 0.0754 AC: 5048 AN: 66922 Hom.: 442 Cov.: 0 AF XY: 0.0812 AC XY: 2404 AN XY: 29604

Gnomad4 AFR AF: 0.248

Gnomad4 AMR AF: 0.0526

Gnomad4 ASJ AF: 0.00187

Gnomad4 EAS AF: 0.00782

Gnomad4 SAS AF: 0.00229

Gnomad4 FIN AF: 0.000888

Gnomad4 NFE AF: 0.00386

Gnomad4 OTH AF: 0.0547

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;