Genetic Variant HMBS:c.33+127_33+135dupTTTTTTTTT (chr11-119085172-C-CTTTTTTTTT) – 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+127_33+135dupTTTTTTTTT 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 0.015 ( 153 hom., cov: 0)

Exomes 𝑓: 0.0098 ( 444 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.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0146 (973/66774) while in subpopulation EAS AF = 0.0449 (63/1404). AF 95% confidence interval is 0.036. There are 153 homozygotes in GnomAd4. There are 417 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High AC in GnomAd4 at 973 SD,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMBS	NM_000190.4 link	c.33+127_33+135dupTTTTTTTTT		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+107insTTTTTTTTT		intron_variant	Intron 1 of 13		NM_000190.4	ENSP00000498786.1		P08397-1

Frequencies

GnomAD3 genomes

AF:

0.0146

AC:

973

AN:

66738

Hom.:

153

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00566

Gnomad AMI

AF:

0.00870

Gnomad AMR

AF:

0.00919

Gnomad ASJ

AF:

0.0154

Gnomad EAS

AF:

0.0449

Gnomad SAS

AF:

0.0183

Gnomad FIN

AF:

0.00979

Gnomad MID

AF:

0.0375

Gnomad NFE

AF:

0.0188

Gnomad OTH

AF:

0.00939

GnomAD4 exome

AF:

0.00977

AC:

7151

AN:

731824

Hom.:

444

Cov.:

AF XY:

0.0101

AC XY:

3644

AN XY:

361966

show subpopulations

African (AFR)

AF:

0.00283

AC:

AN:

18378

American (AMR)

AF:

0.00753

AC:

AN:

11812

Ashkenazi Jewish (ASJ)

AF:

0.00647

AC:

AN:

10362

East Asian (EAS)

AF:

0.0192

AC:

150

AN:

7818

South Asian (SAS)

AF:

0.0136

AC:

682

AN:

50082

European-Finnish (FIN)

AF:

0.0128

AC:

145

AN:

11350

Middle Eastern (MID)

AF:

0.00470

AC:

AN:

1916

European-Non Finnish (NFE)

AF:

0.00966

AC:

5724

AN:

592526

Other (OTH)

AF:

0.00845

AC:

233

AN:

27580

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

185

370

556

741

926

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

248

496

744

992

1240

<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:

0.0146

AC:

973

AN:

66774

Hom.:

153

Cov.:

AF XY:

0.0141

AC XY:

417

AN XY:

29526

show subpopulations

African (AFR)

AF:

0.00565

AC:

104

AN:

18402

American (AMR)

AF:

0.00918

AC:

AN:

4792

Ashkenazi Jewish (ASJ)

AF:

0.0154

AC:

AN:

2142

East Asian (EAS)

AF:

0.0449

AC:

AN:

1404

South Asian (SAS)

AF:

0.0183

AC:

AN:

1308

European-Finnish (FIN)

AF:

0.00979

AC:

AN:

1124

Middle Eastern (MID)

AF:

0.0405

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0188

AC:

679

AN:

36210

Other (OTH)

AF:

0.00932

AC:

AN:

858

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.607

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

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:

0.00

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

(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-CTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT

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