11-119085172-CTTTTTTTTTTTTTTTTTTTTTT-CTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT

Variant summary

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

The NM_000190.4(HMBS):c.33+123_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 0.0017 (13 hom., cov: 0)
  • Exomes 𝑓: 0.0015 (51 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 = 0.00168 (112/66792) while in subpopulation EAS AF= 0.00641 (9/1404). AF 95% confidence interval is 0.00334. There are 13 homozygotes in gnomad4. There are 51 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HMBS	NM_000190.4	c.33+123_33+135dup		intron_variant		ENST00000652429.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HMBS	ENST00000652429.1	c.33+123_33+135dup		intron_variant			NM_000190.4	P3

Frequencies

GnomAD3 genomes AF: 0.00168 AC: 112 AN: 66756 Hom.: 13 Cov.: 0

Gnomad AFR AF: 0.000871

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00104

Gnomad ASJ AF: 0.00233

Gnomad EAS AF: 0.00642

Gnomad SAS AF: 0.00152

Gnomad FIN AF: 0.000890

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00204

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00152 AC: 1114 AN: 732636 Hom.: 51 Cov.: 0 AF XY: 0.00163 AC XY: 589 AN XY: 362388

Gnomad4 AFR exome AF: 0.000490

Gnomad4 AMR exome AF: 0.00161

Gnomad4 ASJ exome AF: 0.000771

Gnomad4 EAS exome AF: 0.00281

Gnomad4 SAS exome AF: 0.00291

Gnomad4 FIN exome AF: 0.00123

Gnomad4 NFE exome AF: 0.00143

Gnomad4 OTH exome AF: 0.00178

GnomAD4 genome AF: 0.00168 AC: 112 AN: 66792 Hom.: 13 Cov.: 0 AF XY: 0.00173 AC XY: 51 AN XY: 29536

Gnomad4 AFR AF: 0.000870

Gnomad4 AMR AF: 0.00104

Gnomad4 ASJ AF: 0.00233

Gnomad4 EAS AF: 0.00641

Gnomad4 SAS AF: 0.00153

Gnomad4 FIN AF: 0.000890

Gnomad4 NFE AF: 0.00204

Gnomad4 OTH AF: 0.00

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;