Genetic Variant HMBS:c.33+126_33+135delTTTTTTTTTT (chr11-119085172-CTTTTTTTTTT-C) – 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+126_33+135delTTTTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0135 in 798,528 control chromosomes in the GnomAD database, including 470 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.075 ( 442 hom., cov: 0)

Exomes 𝑓: 0.0079 ( 28 hom. )

Consequence

HMBS
NM_000190.4 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.83

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.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.242 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMBS	NM_000190.4 link	c.33+126_33+135delTTTTTTTTTT		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+107_33+116delTTTTTTTTTT		intron_variant	Intron 1 of 13		NM_000190.4	ENSP00000498786.1		P08397-1

Frequencies

GnomAD3 genomes

AF:

0.0754

AC:

5044

AN:

66884

Hom.:

440

Cov.:

show subpopulations

Gnomad AFR

AF:

0.248

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0527

Gnomad ASJ

AF:

0.00187

Gnomad EAS

AF:

0.00783

Gnomad SAS

AF:

0.00229

Gnomad FIN

AF:

0.000888

Gnomad MID

AF:

0.0125

Gnomad NFE

AF:

0.00386

Gnomad OTH

AF:

0.0550

GnomAD4 exome

AF:

0.00787

AC:

5757

AN:

731606

Hom.:

AF XY:

0.00732

AC XY:

2650

AN XY:

361880

show subpopulations

African (AFR)

AF:

0.158

AC:

2875

AN:

18144

American (AMR)

AF:

0.0148

AC:

175

AN:

11790

Ashkenazi Jewish (ASJ)

AF:

0.00348

AC:

AN:

10352

East Asian (EAS)

AF:

0.0218

AC:

170

AN:

7798

South Asian (SAS)

AF:

0.00190

AC:

AN:

50090

European-Finnish (FIN)

AF:

0.00123

AC:

AN:

11362

Middle Eastern (MID)

AF:

0.0152

AC:

AN:

1914

European-Non Finnish (NFE)

AF:

0.00328

AC:

1942

AN:

592598

Other (OTH)

AF:

0.0153

AC:

421

AN:

27558

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.423

Heterozygous variant carriers

183

366

548

731

914

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

162

324

486

648

810

<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:

0.0754

AC:

5048

AN:

66922

Hom.:

442

Cov.:

AF XY:

0.0812

AC XY:

2404

AN XY:

29604

show subpopulations

African (AFR)

AF:

0.248

AC:

4588

AN:

18500

American (AMR)

AF:

0.0526

AC:

253

AN:

4810

Ashkenazi Jewish (ASJ)

AF:

0.00187

AC:

AN:

2142

East Asian (EAS)

AF:

0.00782

AC:

AN:

1406

South Asian (SAS)

AF:

0.00229

AC:

AN:

1308

European-Finnish (FIN)

AF:

0.000888

AC:

AN:

1126

Middle Eastern (MID)

AF:

0.0135

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00386

AC:

140

AN:

36236

Other (OTH)

AF:

0.0547

AC:

AN:

860

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.571

Heterozygous variant carriers

153

306

458

611

764

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

184

230

<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:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.8

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Publications

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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