Genetic Variant HMBS:c.33+128_33+135delTTTTTTTT (chr11-119085172-CTTTTTTTT-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_000190.4(HMBS):c.33+128_33+135delTTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00837 in 729,900 control chromosomes in the GnomAD database, including 4 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 0.0064 ( 4 hom., cov: 0)

Exomes 𝑓: 0.0084 ( 4 hom. )

Failed GnomAD Quality Control

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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMBS	NM_000190.4 link	c.33+128_33+135delTTTTTTTT		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+114delTTTTTTTT		intron_variant	Intron 1 of 13		NM_000190.4	ENSP00000498786.1		P08397-1

Frequencies

GnomAD3 genomes

AF:

0.00643

AC:

429

AN:

66764

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00261

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00856

Gnomad ASJ

AF:

0.00560

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00457

Gnomad FIN

AF:

0.000887

Gnomad MID

AF:

0.0125

Gnomad NFE

AF:

0.00858

Gnomad OTH

AF:

0.0106

GnomAD4 exome

AF:

0.00837

AC:

6107

AN:

729900

Hom.:

AF XY:

0.00811

AC XY:

2928

AN XY:

361004

show subpopulations

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

African (AFR)

AF:

0.00683

AC:

125

AN:

18302

American (AMR)

AF:

0.00493

AC:

AN:

11770

Ashkenazi Jewish (ASJ)

AF:

0.00619

AC:

AN:

10336

East Asian (EAS)

AF:

0.0125

AC:

AN:

7782

South Asian (SAS)

AF:

0.00556

AC:

277

AN:

49854

European-Finnish (FIN)

AF:

0.00406

AC:

AN:

11342

Middle Eastern (MID)

AF:

0.00261

AC:

AN:

1914

European-Non Finnish (NFE)

AF:

0.00878

AC:

5187

AN:

591086

Other (OTH)

AF:

0.00901

AC:

248

AN:

27514

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.369

Heterozygous variant carriers

304

608

911

1215

1519

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

228

456

684

912

1140

<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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00642

AC:

429

AN:

66800

Hom.:

Cov.:

AF XY:

0.00623

AC XY:

184

AN XY:

29538

show subpopulations

African (AFR)

AF:

0.00261

AC:

AN:

18404

American (AMR)

AF:

0.00855

AC:

AN:

4796

Ashkenazi Jewish (ASJ)

AF:

0.00560

AC:

AN:

2142

East Asian (EAS)

AF:

0.00

AC:

AN:

1404

South Asian (SAS)

AF:

0.00459

AC:

AN:

1308

European-Finnish (FIN)

AF:

0.000887

AC:

AN:

1128

Middle Eastern (MID)

AF:

0.0135

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00858

AC:

311

AN:

36226

Other (OTH)

AF:

0.0105

AC:

AN:

858

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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