11-119085172-CTTTTTTTTTTTTTTTTTTTTTT-CTTTTTTTTTTTTTT

Variant summary

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

The NM_000190.4(HMBS):c.33+128_33+135del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00837 in 729,900 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 0.0064 (4 hom., cov: 0)
  • Exomes 𝑓: 0.0084 (4 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.

• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.00837 (6107/729900) while in subpopulation EAS AF= 0.0125 (97/7782). AF 95% confidence interval is 0.0105. There are 4 homozygotes in gnomad4_exome. There are 2928 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HMBS	NM_000190.4	c.33+128_33+135del		intron_variant		ENST00000652429.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HMBS	ENST00000652429.1	c.33+128_33+135del		intron_variant			NM_000190.4	P3

Frequencies

GnomAD3 genomes AF: 0.00643 AC: 429 AN: 66764 Hom.: 4 Cov.: 0

Gnomad AFR AF: 0.00261

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00856

Gnomad ASJ AF: 0.00560

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00457

Gnomad FIN AF: 0.000887

Gnomad MID AF: 0.0125

Gnomad NFE AF: 0.00858

Gnomad OTH AF: 0.0106

GnomAD4 exome AF: 0.00837 AC: 6107 AN: 729900 Hom.: 4 AF XY: 0.00811 AC XY: 2928 AN XY: 361004

Gnomad4 AFR exome AF: 0.00683

Gnomad4 AMR exome AF: 0.00493

Gnomad4 ASJ exome AF: 0.00619

Gnomad4 EAS exome AF: 0.0125

Gnomad4 SAS exome AF: 0.00556

Gnomad4 FIN exome AF: 0.00406

Gnomad4 NFE exome AF: 0.00878

Gnomad4 OTH exome AF: 0.00901

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00642 AC: 429 AN: 66800 Hom.: 4 Cov.: 0 AF XY: 0.00623 AC XY: 184 AN XY: 29538

Gnomad4 AFR AF: 0.00261

Gnomad4 AMR AF: 0.00855

Gnomad4 ASJ AF: 0.00560

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00459

Gnomad4 FIN AF: 0.000887

Gnomad4 NFE AF: 0.00858

Gnomad4 OTH AF: 0.0105

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;