11-119085172-CTTTTTTTTTTTTTTTTTTTTTT-CTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT

Variant summary

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

The NM_000190.4(HMBS):c.33+124_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 0.0046 (44 hom., cov: 0)
  • Exomes 𝑓: 0.0028 (86 hom.)
  • Failed GnomAD Quality Control
• 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 sas. gnomad4 allele frequency = 0.00463 (309/66782) while in subpopulation SAS AF= 0.00841 (11/1308). AF 95% confidence interval is 0.00583. There are 44 homozygotes in gnomad4. There are 135 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 44 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HMBS	NM_000190.4	c.33+124_33+135dup		intron_variant		ENST00000652429.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HMBS	ENST00000652429.1	c.33+124_33+135dup		intron_variant			NM_000190.4	P3

Frequencies

GnomAD3 genomes AF: 0.00463 AC: 309 AN: 66746 Hom.: 44 Cov.: 0

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.0109

Gnomad AMR AF: 0.00313

Gnomad ASJ AF: 0.00327

Gnomad EAS AF: 0.00285

Gnomad SAS AF: 0.00838

Gnomad FIN AF: 0.000891

Gnomad MID AF: 0.0125

Gnomad NFE AF: 0.00652

Gnomad OTH AF: 0.00235

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00277 AC: 2029 AN: 732450 Hom.: 86 Cov.: 0 AF XY: 0.00294 AC XY: 1064 AN XY: 362270

Gnomad4 AFR exome AF: 0.000707

Gnomad4 AMR exome AF: 0.00195

Gnomad4 ASJ exome AF: 0.00212

Gnomad4 EAS exome AF: 0.00397

Gnomad4 SAS exome AF: 0.00577

Gnomad4 FIN exome AF: 0.00405

Gnomad4 NFE exome AF: 0.00258

Gnomad4 OTH exome AF: 0.00254

GnomAD4 genome AF: 0.00463 AC: 309 AN: 66782 Hom.: 44 Cov.: 0 AF XY: 0.00457 AC XY: 135 AN XY: 29524

Gnomad4 AFR AF: 0.00147

Gnomad4 AMR AF: 0.00313

Gnomad4 ASJ AF: 0.00327

Gnomad4 EAS AF: 0.00285

Gnomad4 SAS AF: 0.00841

Gnomad4 FIN AF: 0.000891

Gnomad4 NFE AF: 0.00652

Gnomad4 OTH AF: 0.00233

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;