Genetic Variant HMBS:c.33+131_33+135dupTTTTT (chr11-119085172-C-CTTTTT) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The NM_000190.4(HMBS):c.33+131_33+135dupTTTTT 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 0.031 ( 285 hom., cov: 0)

Exomes 𝑓: 0.021 ( 1092 hom. )

Consequence

HMBS
NM_000190.4 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.497

Publications

0 publications found

Variant links:

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

HMBS links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0309 (2059/66714) while in subpopulation NFE AF = 0.0397 (1435/36188). AF 95% confidence interval is 0.0379. There are 285 homozygotes in GnomAd4. There are 821 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High AC in GnomAd4 at 2059 SD,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMBS	NM_000190.4 link	c.33+131_33+135dupTTTTT		intron_variant	Intron 1 of 13	ENST00000652429.1	NP_000181.2	P08397-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMBS	ENST00000652429.1 link	c.33+106_33+107insTTTTT		intron_variant	Intron 1 of 13		NM_000190.4	ENSP00000498786.1		P08397-1

Frequencies

GnomAD3 genomes

AF:

0.0309

AC:

2059

AN:

66678

Hom.:

285

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0227

Gnomad AMI

AF:

0.0217

Gnomad AMR

AF:

0.0203

Gnomad ASJ

AF:

0.0135

Gnomad EAS

AF:

0.0292

Gnomad SAS

AF:

0.00534

Gnomad FIN

AF:

0.00357

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0397

Gnomad OTH

AF:

0.0235

GnomAD4 exome

AF:

0.0213

AC:

15561

AN:

729152

Hom.:

1092

Cov.:

AF XY:

0.0212

AC XY:

7635

AN XY:

360628

show subpopulations

African (AFR)

AF:

0.00670

AC:

123

AN:

18364

American (AMR)

AF:

0.0169

AC:

199

AN:

11792

Ashkenazi Jewish (ASJ)

AF:

0.0170

AC:

176

AN:

10336

East Asian (EAS)

AF:

0.0427

AC:

332

AN:

7774

South Asian (SAS)

AF:

0.0257

AC:

1280

AN:

49858

European-Finnish (FIN)

AF:

0.0259

AC:

293

AN:

11292

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

1912

European-Non Finnish (NFE)

AF:

0.0213

AC:

12591

AN:

590316

Other (OTH)

AF:

0.0197

AC:

541

AN:

27508

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.443

Heterozygous variant carriers

418

835

1253

1670

2088

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

474

948

1422

1896

2370

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0309

AC:

2059

AN:

66714

Hom.:

285

Cov.:

AF XY:

0.0278

AC XY:

821

AN XY:

29494

show subpopulations

African (AFR)

AF:

0.0226

AC:

416

AN:

18380

American (AMR)

AF:

0.0203

AC:

AN:

4780

Ashkenazi Jewish (ASJ)

AF:

0.0135

AC:

AN:

2142

East Asian (EAS)

AF:

0.0292

AC:

AN:

1404

South Asian (SAS)

AF:

0.00536

AC:

AN:

1306

European-Finnish (FIN)

AF:

0.00357

AC:

AN:

1122

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0397

AC:

1435

AN:

36188

Other (OTH)

AF:

0.0233

AC:

AN:

858

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.590

Heterozygous variant carriers

142

190

237

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0131

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.50

Splicing

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

Publications

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11-119085172-CTTTTTTTTTTTTTTTTTTTTTT-CTTTTTTTTTTTTTTTTTTTTTTTTTTT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over