Genetic Variant HMBS:c.33+129_33+135dupTTTTTTT (chr11-119085172-C-CTTTTTTT) – ACMG Classification: Benign (-8 pts)

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

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 link	c.33+129_33+135dupTTTTTTT		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+107insTTTTTTT		intron_variant	Intron 1 of 13		NM_000190.4	ENSP00000498786.1		P08397-1

Frequencies

GnomAD3 genomes

AF:

0.0542

AC:

3610

AN:

66640

Hom.:

672

Cov.:

show subpopulations

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.:

AF XY:

0.0214

AC XY:

7730

AN XY:

361198

show subpopulations

African (AFR)

AF:

0.00463

AC:

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:

AN:

1916

European-Non Finnish (NFE)

AF:

0.0199

AC:

11768

AN:

591264

Other (OTH)

AF:

0.0218

AC:

599

AN:

27520

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

379

757

1136

1514

1893

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

462

924

1386

1848

2310

<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:

0.0541

AC:

3610

AN:

66678

Hom.:

672

Cov.:

AF XY:

0.0530

AC XY:

1561

AN XY:

29462

show subpopulations

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:

AN:

1112

Middle Eastern (MID)

AF:

0.0270

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0682

AC:

2467

AN:

36172

Other (OTH)

AF:

0.0445

AC:

AN:

854

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.620

Heterozygous variant carriers

148

223

297

371

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<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:

0.0155

Hom.:

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)

(source)

Splicing

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

Publications

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11-119085172-CTTTTTTTTTTTTTTTTTTTTTT-CTTTTTTTTTTTTTTTTTTTTTTTTTTTTT

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