11-119085172-CTTTTTTTTTTTTTTTTTTTTTT-CTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT

Variant summary

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

The NM_000190.4(HMBS):c.33+127_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 0.015 (153 hom., cov: 0)
  • Exomes 𝑓: 0.0098 (444 hom.)
• 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 eas. gnomad4 allele frequency = 0.0146 (973/66774) while in subpopulation EAS AF= 0.0449 (63/1404). AF 95% confidence interval is 0.036. There are 153 homozygotes in gnomad4. There are 417 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 153 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HMBS	NM_000190.4	c.33+127_33+135dup		intron_variant		ENST00000652429.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HMBS	ENST00000652429.1	c.33+127_33+135dup		intron_variant			NM_000190.4	P3

Frequencies

GnomAD3 genomes AF: 0.0146 AC: 973 AN: 66738 Hom.: 153 Cov.: 0

Gnomad AFR AF: 0.00566

Gnomad AMI AF: 0.00870

Gnomad AMR AF: 0.00919

Gnomad ASJ AF: 0.0154

Gnomad EAS AF: 0.0449

Gnomad SAS AF: 0.0183

Gnomad FIN AF: 0.00979

Gnomad MID AF: 0.0375

Gnomad NFE AF: 0.0188

Gnomad OTH AF: 0.00939

GnomAD4 exome AF: 0.00977 AC: 7151 AN: 731824 Hom.: 444 Cov.: 0 AF XY: 0.0101 AC XY: 3644 AN XY: 361966

Gnomad4 AFR exome AF: 0.00283

Gnomad4 AMR exome AF: 0.00753

Gnomad4 ASJ exome AF: 0.00647

Gnomad4 EAS exome AF: 0.0192

Gnomad4 SAS exome AF: 0.0136

Gnomad4 FIN exome AF: 0.0128

Gnomad4 NFE exome AF: 0.00966

Gnomad4 OTH exome AF: 0.00845

GnomAD4 genome AF: 0.0146 AC: 973 AN: 66774 Hom.: 153 Cov.: 0 AF XY: 0.0141 AC XY: 417 AN XY: 29526

Gnomad4 AFR AF: 0.00565

Gnomad4 AMR AF: 0.00918

Gnomad4 ASJ AF: 0.0154

Gnomad4 EAS AF: 0.0449

Gnomad4 SAS AF: 0.0183

Gnomad4 FIN AF: 0.00979

Gnomad4 NFE AF: 0.0188

Gnomad4 OTH AF: 0.00932

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;