Genetic Variant HMBS:c.33+125_33+135delTTTTTTTTTTT (chr11-119085172-CTTTTTTTTTTT-C) – 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+125_33+135delTTTTTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0124 in 798,278 control chromosomes in the GnomAD database, including 28 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.010 ( 11 hom., cov: 0)

Exomes 𝑓: 0.013 ( 17 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:

Genome browser will be placed here

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 = 0.01 (671/66818) while in subpopulation NFE AF = 0.0138 (501/36242). AF 95% confidence interval is 0.0128. There are 11 homozygotes in GnomAd4. There are 272 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High AC in GnomAd4 at 671 SD,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMBS	NM_000190.4 link	c.33+125_33+135delTTTTTTTTTTT		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+117delTTTTTTTTTTT		intron_variant	Intron 1 of 13		NM_000190.4	ENSP00000498786.1		P08397-1

Frequencies

GnomAD3 genomes

AF:

0.0100

AC:

671

AN:

66782

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00572

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00855

Gnomad ASJ

AF:

0.000467

Gnomad EAS

AF:

0.00214

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00533

Gnomad MID

AF:

0.0250

Gnomad NFE

AF:

0.0138

Gnomad OTH

AF:

0.0141

GnomAD4 exome

AF:

0.0127

AC:

9258

AN:

731460

Hom.:

AF XY:

0.0122

AC XY:

4427

AN XY:

361808

show subpopulations

African (AFR)

AF:

0.0450

AC:

817

AN:

18142

American (AMR)

AF:

0.0119

AC:

140

AN:

11770

Ashkenazi Jewish (ASJ)

AF:

0.00174

AC:

AN:

10360

East Asian (EAS)

AF:

0.0109

AC:

AN:

7810

South Asian (SAS)

AF:

0.00124

AC:

AN:

50108

European-Finnish (FIN)

AF:

0.00484

AC:

AN:

11358

Middle Eastern (MID)

AF:

0.00939

AC:

AN:

1916

European-Non Finnish (NFE)

AF:

0.0130

AC:

7685

AN:

592444

Other (OTH)

AF:

0.0137

AC:

378

AN:

27552

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.419

Heterozygous variant carriers

292

584

876

1168

1460

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

344

688

1032

1376

1720

<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:

0.0100

AC:

671

AN:

66818

Hom.:

Cov.:

AF XY:

0.00921

AC XY:

272

AN XY:

29548

show subpopulations

African (AFR)

AF:

0.00571

AC:

105

AN:

18404

American (AMR)

AF:

0.00854

AC:

AN:

4800

Ashkenazi Jewish (ASJ)

AF:

0.000467

AC:

AN:

2142

East Asian (EAS)

AF:

0.00214

AC:

AN:

1404

South Asian (SAS)

AF:

0.00

AC:

AN:

1308

European-Finnish (FIN)

AF:

0.00533

AC:

AN:

1126

Middle Eastern (MID)

AF:

0.0270

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0138

AC:

501

AN:

36242

Other (OTH)

AF:

0.0140

AC:

AN:

858

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.566

Heterozygous variant carriers

114

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

11-119085172-CTTTTTTTTTTTTTTTTTTTTTT-CTTTTTTTTTTT

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