NM_000190.4:c.33+129_33+135dupTTTTTTT

Variant names:

• chr11-119085172-C-CTTTTTTT
• rs549270240
• NM_000190.4:c.33+129_33+135dupTTTTTTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_000190.4(HMBS):​c.33+129_33+135dupTTTTTTT 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 0.054 (672 hom., cov: 0)
  • Exomes 𝑓: 0.021 (1223 hom.)
• Consequence: HMBS NM_000190.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.497
• 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: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.157 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMBS	NM_000190.4	c.33+129_33+135dupTTTTTTT		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+106_33+107insTTTTTTT		intron_variant	Intron 1 of 13		NM_000190.4	ENSP00000498786.1

Frequencies

GnomAD3 genomes AF: 0.0542 AC: 3610 AN: 66640 Hom.: 672 Cov.: 0

Gnomad AFR AF: 0.0199

Gnomad AMI AF: 0.0326

Gnomad AMR AF: 0.0381

Gnomad ASJ AF: 0.0763

Gnomad EAS AF: 0.176

Gnomad SAS AF: 0.0932

Gnomad FIN AF: 0.00899

Gnomad MID AF: 0.0256

Gnomad NFE AF: 0.0682

Gnomad OTH AF: 0.0448

GnomAD4 exome AF: 0.0207 AC: 15124 AN: 730302 Hom.: 1223 Cov.: 0 AF XY: 0.0214 AC XY: 7730 AN XY: 361198

African (AFR) AF: 0.00463 AC: 85 AN: 18374

American (AMR) AF: 0.0152 AC: 179 AN: 11804

Ashkenazi Jewish (ASJ) AF: 0.0159 AC: 165 AN: 10346

East Asian (EAS) AF: 0.0412 AC: 321 AN: 7794

South Asian (SAS) AF: 0.0331 AC: 1655 AN: 49976

European-Finnish (FIN) AF: 0.0283 AC: 320 AN: 11308

Middle Eastern (MID) AF: 0.0167 AC: 32 AN: 1916

European-Non Finnish (NFE) AF: 0.0199 AC: 11768 AN: 591264

Other (OTH) AF: 0.0218 AC: 599 AN: 27520

GnomAD4 genome AF: 0.0541 AC: 3610 AN: 66678 Hom.: 672 Cov.: 0 AF XY: 0.0530 AC XY: 1561 AN XY: 29462

African (AFR) AF: 0.0199 AC: 366 AN: 18392

American (AMR) AF: 0.0381 AC: 182 AN: 4782

Ashkenazi Jewish (ASJ) AF: 0.0763 AC: 163 AN: 2136

East Asian (EAS) AF: 0.175 AC: 246 AN: 1402

South Asian (SAS) AF: 0.0935 AC: 121 AN: 1294

European-Finnish (FIN) AF: 0.00899 AC: 10 AN: 1112

Middle Eastern (MID) AF: 0.0270 AC: 2 AN: 74

European-Non Finnish (NFE) AF: 0.0682 AC: 2467 AN: 36172

Other (OTH) AF: 0.0445 AC: 38 AN: 854

Alfa AF: 0.0155 Hom.: 67

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.50
Mutation Taster		=100/0	polymorphism (auto)

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;