11-119085172-CTTTTTTTTTTTTTTTTTTTTTT-CTTTTTTTTTTTTTTTTTTT

Variant summary

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

The NM_000190.4(HMBS):c.33+133_33+135del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.144 in 710,748 control chromosomes in the GnomAD database, including 1,849 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.24 (839 hom., cov: 0)
  • Exomes 𝑓: 0.14 (1849 hom.)
  • Failed GnomAD Quality Control
• 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: GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.152 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HMBS	NM_000190.4	c.33+133_33+135del		intron_variant		ENST00000652429.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HMBS	ENST00000652429.1	c.33+133_33+135del		intron_variant			NM_000190.4	P3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 15667 AN: 64316 Hom.: 838 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.194

Gnomad AMI AF: 0.280

Gnomad AMR AF: 0.233

Gnomad ASJ AF: 0.266

Gnomad EAS AF: 0.153

Gnomad SAS AF: 0.214

Gnomad FIN AF: 0.0945

Gnomad MID AF: 0.338

Gnomad NFE AF: 0.278

Gnomad OTH AF: 0.256

GnomAD4 exome AF: 0.144 AC: 102378 AN: 710748 Hom.: 1849 AF XY: 0.142 AC XY: 49823 AN XY: 350610

Gnomad4 AFR exome AF: 0.115

Gnomad4 AMR exome AF: 0.0933

Gnomad4 ASJ exome AF: 0.110

Gnomad4 EAS exome AF: 0.0656

Gnomad4 SAS exome AF: 0.106

Gnomad4 FIN exome AF: 0.0717

Gnomad4 NFE exome AF: 0.153

Gnomad4 OTH exome AF: 0.132

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.244 AC: 15671 AN: 64348 Hom.: 839 Cov.: 0 AF XY: 0.237 AC XY: 6760 AN XY: 28548

Gnomad4 AFR AF: 0.194

Gnomad4 AMR AF: 0.233

Gnomad4 ASJ AF: 0.266

Gnomad4 EAS AF: 0.153

Gnomad4 SAS AF: 0.211

Gnomad4 FIN AF: 0.0945

Gnomad4 NFE AF: 0.278

Gnomad4 OTH AF: 0.255

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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;