11-119085172-CTTTTTTTTTTTTTTTTTTTTTT-CTTTTTTTT

Position:

• chr11-119085172-CTTTTTTTTTTTTTTTTTTTTTT-CTTTTTTTT

Variant summary

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

The NM_000190.4(HMBS):​c.33+122_33+135del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00955 in 797,442 control chromosomes in the GnomAD database, including 7 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00040 (1 hom., cov: 0)
  • Exomes 𝑓: 0.010 (6 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 mid. gnomad4_exome allele frequency = 0.0104 (7590/730646) while in subpopulation MID AF= 0.0157 (30/1916). AF 95% confidence interval is 0.0113. There are 6 homozygotes in gnomad4_exome. There are 3789 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 6 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HMBS	NM_000190.4	c.33+122_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+122_33+135del		intron_variant			NM_000190.4	ENSP00000498786	P3

Frequencies

GnomAD3 genomes AF: 0.000419 AC: 28 AN: 66760 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.0000544

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000418

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000713

Gnomad SAS AF: 0.00381

Gnomad FIN AF: 0.00266

Gnomad MID AF: 0.0125

Gnomad NFE AF: 0.000386

Gnomad OTH AF: 0.00117

GnomAD4 exome AF: 0.0104 AC: 7590 AN: 730646 Hom.: 6 AF XY: 0.0105 AC XY: 3789 AN XY: 361292

Gnomad4 AFR exome AF: 0.00305

Gnomad4 AMR exome AF: 0.00602

Gnomad4 ASJ exome AF: 0.0265

Gnomad4 EAS exome AF: 0.00102

Gnomad4 SAS exome AF: 0.00912

Gnomad4 FIN exome AF: 0.0251

Gnomad4 NFE exome AF: 0.0103

Gnomad4 OTH exome AF: 0.0113

GnomAD4 genome AF: 0.000404 AC: 27 AN: 66796 Hom.: 1 Cov.: 0 AF XY: 0.000339 AC XY: 10 AN XY: 29536

Gnomad4 AFR AF: 0.0000543

Gnomad4 AMR AF: 0.000417

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000712

Gnomad4 SAS AF: 0.00382

Gnomad4 FIN AF: 0.00266

Gnomad4 NFE AF: 0.000386

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;