11-119085172-CTTTTTTTTTTTTTTTTTTTTTT-CTTTTTTTTTTTTTTT

Position:

• chr11-119085172-CTTTTTTTTTTTTTTTTTTTTTT-CTTTTTTTTTTTTTTT

Variant summary

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

The NM_000190.4(HMBS):​c.33+129_33+135del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00973 in 794,732 control chromosomes in the GnomAD database, including 5 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00085 (0 hom., cov: 0)
  • Exomes 𝑓: 0.011 (5 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 = 0.000853 (57/66804) while in subpopulation EAS AF= 0.00997 (14/1404). AF 95% confidence interval is 0.00603. There are 0 homozygotes in gnomad4. There are 30 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 5 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HMBS	NM_000190.4	c.33+129_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+129_33+135del		intron_variant			NM_000190.4	ENSP00000498786	P3

Frequencies

GnomAD3 genomes AF: 0.000854 AC: 57 AN: 66768 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000381

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000626

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00999

Gnomad SAS AF: 0.00229

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000828

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0105 AC: 7676 AN: 727928 Hom.: 5 AF XY: 0.0106 AC XY: 3825 AN XY: 359898

Gnomad4 AFR exome AF: 0.0120

Gnomad4 AMR exome AF: 0.00786

Gnomad4 ASJ exome AF: 0.00767

Gnomad4 EAS exome AF: 0.0246

Gnomad4 SAS exome AF: 0.0159

Gnomad4 FIN exome AF: 0.00752

Gnomad4 NFE exome AF: 0.0100

Gnomad4 OTH exome AF: 0.0110

GnomAD4 genome AF: 0.000853 AC: 57 AN: 66804 Hom.: 0 Cov.: 0 AF XY: 0.00102 AC XY: 30 AN XY: 29542

Gnomad4 AFR AF: 0.000380

Gnomad4 AMR AF: 0.000626

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00997

Gnomad4 SAS AF: 0.00229

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000828

Gnomad4 OTH AF: 0.00

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;