NM_000190.4:c.33+134_33+135delTT

Variant names:

• chr11-119085172-CTT-C
• rs549270240
• NM_000190.4:c.33+134_33+135delTT

Variant summary

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

The NM_000190.4(HMBS):​c.33+134_33+135delTT 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. 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: 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
• 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+134_33+135delTT		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+108delTT		intron_variant	Intron 1 of 13		NM_000190.4	ENSP00000498786.1

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

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

African (AFR) AF: 0.0454 AC: 811 AN: 17848

American (AMR) AF: 0.0393 AC: 441 AN: 11214

Ashkenazi Jewish (ASJ) AF: 0.0321 AC: 323 AN: 10062

East Asian (EAS) AF: 0.0164 AC: 127 AN: 7730

South Asian (SAS) AF: 0.0304 AC: 1446 AN: 47498

European-Finnish (FIN) AF: 0.0189 AC: 208 AN: 10984

Middle Eastern (MID) AF: 0.0445 AC: 83 AN: 1866

European-Non Finnish (NFE) AF: 0.0372 AC: 21650 AN: 582656

Other (OTH) AF: 0.0346 AC: 934 AN: 26958

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

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

African (AFR) AF: 0.0699 AC: 1272 AN: 18198

American (AMR) AF: 0.0370 AC: 176 AN: 4754

Ashkenazi Jewish (ASJ) AF: 0.0583 AC: 123 AN: 2108

East Asian (EAS) AF: 0.0128 AC: 18 AN: 1404

South Asian (SAS) AF: 0.0285 AC: 37 AN: 1296

European-Finnish (FIN) AF: 0.00622 AC: 7 AN: 1126

Middle Eastern (MID) AF: 0.0139 AC: 1 AN: 72

European-Non Finnish (NFE) AF: 0.0252 AC: 910 AN: 36084

Other (OTH) AF: 0.0404 AC: 34 AN: 842

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 67

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.39
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs549270240; hg19: chr11-118955882;