11-119085172-CTTTTTTTTTTTTTTTTTTTTTT-CTTTTTTTTTTTTTTTTTTTT

Position:

• chr11-119085172-CTTTTTTTTTTTTTTTTTTTTTT-CTTTTTTTTTTTTTTTTTTTT

Variant summary

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

The NM_000190.4(HMBS):​c.33+134_33+135del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0363 in 716,816 control chromosomes in the GnomAD database, including 313 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.039 (28 hom., cov: 0)
  • Exomes 𝑓: 0.036 (313 hom.)
  • Failed GnomAD Quality Control
• Consequence: HMBS NM_000190.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.394

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 afr. gnomad4_exome allele frequency = 0.0363 (26023/716816) while in subpopulation AFR AF= 0.0454 (811/17848). AF 95% confidence interval is 0.0428. There are 313 homozygotes in gnomad4_exome. There are 12544 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 313 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HMBS	NM_000190.4	c.33+134_33+135del		intron_variant		ENST00000652429.1	NP_000181.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HMBS	ENST00000652429.1	c.33+134_33+135del		intron_variant			NM_000190.4	ENSP00000498786	P3

Frequencies

GnomAD3 genomes AF: 0.0390 AC: 2589 AN: 66308 Hom.: 29 Cov.: 0

Gnomad AFR AF: 0.0699

Gnomad AMI AF: 0.0239

Gnomad AMR AF: 0.0375

Gnomad ASJ AF: 0.0583

Gnomad EAS AF: 0.0128

Gnomad SAS AF: 0.0292

Gnomad FIN AF: 0.00622

Gnomad MID AF: 0.0128

Gnomad NFE AF: 0.0252

Gnomad OTH AF: 0.0407

GnomAD4 exome AF: 0.0363 AC: 26023 AN: 716816 Hom.: 313 AF XY: 0.0354 AC XY: 12544 AN XY: 353972

Gnomad4 AFR exome AF: 0.0454

Gnomad4 AMR exome AF: 0.0393

Gnomad4 ASJ exome AF: 0.0321

Gnomad4 EAS exome AF: 0.0164

Gnomad4 SAS exome AF: 0.0304

Gnomad4 FIN exome AF: 0.0189

Gnomad4 NFE exome AF: 0.0372

Gnomad4 OTH exome AF: 0.0346

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0390 AC: 2589 AN: 66344 Hom.: 28 Cov.: 0 AF XY: 0.0390 AC XY: 1144 AN XY: 29358

Gnomad4 AFR AF: 0.0699

Gnomad4 AMR AF: 0.0370

Gnomad4 ASJ AF: 0.0583

Gnomad4 EAS AF: 0.0128

Gnomad4 SAS AF: 0.0285

Gnomad4 FIN AF: 0.00622

Gnomad4 NFE AF: 0.0252

Gnomad4 OTH AF: 0.0404

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;