Genetic Variant HMBS:c.33+133_33+135delTTT (chr11-119085172-CTTT-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+133_33+135delTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.144 in 710,748 control chromosomes in the GnomAD database, including 1,849 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.24 ( 839 hom., cov: 0)

Exomes 𝑓: 0.14 ( 1849 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BA1

GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.152 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMBS	NM_000190.4 link	c.33+133_33+135delTTT		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+109delTTT		intron_variant	Intron 1 of 13		NM_000190.4	ENSP00000498786.1		P08397-1

Frequencies

GnomAD3 genomes

AF:

0.244

AC:

15667

AN:

64316

Hom.:

838

Cov.:

show subpopulations

Gnomad AFR

AF:

0.194

Gnomad AMI

AF:

0.280

Gnomad AMR

AF:

0.233

Gnomad ASJ

AF:

0.266

Gnomad EAS

AF:

0.153

Gnomad SAS

AF:

0.214

Gnomad FIN

AF:

0.0945

Gnomad MID

AF:

0.338

Gnomad NFE

AF:

0.278

Gnomad OTH

AF:

0.256

GnomAD4 exome

AF:

0.144

AC:

102378

AN:

710748

Hom.:

1849

AF XY:

0.142

AC XY:

49823

AN XY:

350610

show subpopulations

African (AFR)

AF:

0.115

AC:

2036

AN:

17680

American (AMR)

AF:

0.0933

AC:

1037

AN:

11114

Ashkenazi Jewish (ASJ)

AF:

0.110

AC:

1100

AN:

9988

East Asian (EAS)

AF:

0.0656

AC:

500

AN:

7624

South Asian (SAS)

AF:

0.106

AC:

4979

AN:

46820

European-Finnish (FIN)

AF:

0.0717

AC:

772

AN:

10770

Middle Eastern (MID)

AF:

0.131

AC:

243

AN:

1860

European-Non Finnish (NFE)

AF:

0.153

AC:

88185

AN:

578150

Other (OTH)

AF:

0.132

AC:

3526

AN:

26742

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.415

Heterozygous variant carriers

3432

6864

10296

13728

17160

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4002

8004

12006

16008

20010

<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:

0.244

AC:

15671

AN:

64348

Hom.:

839

Cov.:

AF XY:

0.237

AC XY:

6760

AN XY:

28548

show subpopulations

African (AFR)

AF:

0.194

AC:

3500

AN:

17998

American (AMR)

AF:

0.233

AC:

1074

AN:

4618

Ashkenazi Jewish (ASJ)

AF:

0.266

AC:

538

AN:

2026

East Asian (EAS)

AF:

0.153

AC:

212

AN:

1384

South Asian (SAS)

AF:

0.211

AC:

264

AN:

1250

European-Finnish (FIN)

AF:

0.0945

AC:

103

AN:

1090

Middle Eastern (MID)

AF:

0.382

AC:

AN:

European-Non Finnish (NFE)

AF:

0.278

AC:

9617

AN:

34636

Other (OTH)

AF:

0.255

AC:

214

AN:

838

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

545

1090

1634

2179

2724

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.0833

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

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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11-119085172-CTTTTTTTTTTTTTTTTTTTTTT-CTTTTTTTTTTTTTTTTTTT

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