11-119085172-CTTTTTTTTTTTTTTTTTTTTTT-CTTTT

Variant names:

• chr11-119085172-CTTTTTTTTTTTTTTTTTT-C
• rs549270240
• NM_000190.4:c.33+118_33+135delTTTTTTTTTTTTTTTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000190.4(HMBS):​c.33+118_33+135delTTTTTTTTTTTTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 732,808 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: HMBS NM_000190.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.83
• Publications: 0 publications found

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]

HMBS Gene-Disease associations (from GenCC):

• acute intermittent porphyria

  Inheritance: SD, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMBS	NM_000190.4	c.33+118_33+135delTTTTTTTTTTTTTTTTTT		intron_variant	Intron 1 of 13	ENST00000652429.1	NP_000181.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMBS	ENST00000652429.1	c.33+107_33+124delTTTTTTTTTTTTTTTTTT		intron_variant	Intron 1 of 13		NM_000190.4	ENSP00000498786.1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 0.0000109 AC: 8 AN: 732808 Hom.: 0 AF XY: 0.0000138 AC XY: 5 AN XY: 362462

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000109 AC: 2 AN: 18384

American (AMR) AF: 0.00 AC: 0 AN: 11818

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10372

East Asian (EAS) AF: 0.00 AC: 0 AN: 7824

South Asian (SAS) AF: 0.0000199 AC: 1 AN: 50138

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 11370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1920

European-Non Finnish (NFE) AF: 0.00000843 AC: 5 AN: 593376

Other (OTH) AF: 0.00 AC: 0 AN: 27606

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00263586), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 0

Alfa AF: 0.00 Hom.: 67

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.8

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs549270240; hg19: chr11-118955882;