11-119085172-CTTTTTTTTTTTTTTTTTTTTTT-CTTTTTTTTTTTTT

Position:

• chr11-119085172-CTTTTTTTTTTTTTTTTTTTTTT-CTTTTTTTTTTTTT

Variant summary

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

The NM_000190.4(HMBS):​c.33+127_33+135del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00331 in 798,048 control chromosomes in the GnomAD database, including 4 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0015 (3 hom., cov: 0)
  • Exomes 𝑓: 0.0035 (1 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.

• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00148 (99/66806) while in subpopulation EAS AF= 0.0156 (22/1406). AF 95% confidence interval is 0.0106. There are 3 homozygotes in gnomad4. There are 45 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HMBS	NM_000190.4	c.33+127_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+127_33+135del		intron_variant			NM_000190.4	ENSP00000498786	P3

Frequencies

GnomAD3 genomes AF: 0.00148 AC: 99 AN: 66770 Hom.: 3 Cov.: 0

Gnomad AFR AF: 0.00305

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00146

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0157

Gnomad SAS AF: 0.00229

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000276

Gnomad OTH AF: 0.00117

GnomAD4 exome AF: 0.00348 AC: 2544 AN: 731242 Hom.: 1 AF XY: 0.00344 AC XY: 1246 AN XY: 361698

Gnomad4 AFR exome AF: 0.0133

Gnomad4 AMR exome AF: 0.00322

Gnomad4 ASJ exome AF: 0.00232

Gnomad4 EAS exome AF: 0.0184

Gnomad4 SAS exome AF: 0.00186

Gnomad4 FIN exome AF: 0.00176

Gnomad4 NFE exome AF: 0.00314

Gnomad4 OTH exome AF: 0.00414

GnomAD4 genome AF: 0.00148 AC: 99 AN: 66806 Hom.: 3 Cov.: 0 AF XY: 0.00152 AC XY: 45 AN XY: 29538

Gnomad4 AFR AF: 0.00304

Gnomad4 AMR AF: 0.00146

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0156

Gnomad4 SAS AF: 0.00229

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000276

Gnomad4 OTH AF: 0.00117

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;