Genetic Variant HMBS:c.33+132_33+135delTTTT (chr11-119085172-CTTTT-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+132_33+135delTTTT 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 0.034 ( 57 hom., cov: 0)

Exomes 𝑓: 0.090 ( 348 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+132_33+135delTTTT		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+110delTTTT		intron_variant	Intron 1 of 13		NM_000190.4	ENSP00000498786.1		P08397-1

Frequencies

GnomAD3 genomes

AF:

0.0340

AC:

2262

AN:

66604

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.113

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0184

Gnomad ASJ

AF:

0.000467

Gnomad EAS

AF:

0.0257

Gnomad SAS

AF:

0.00381

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00160

Gnomad OTH

AF:

0.0270

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0898

AC:

63958

AN:

712200

Hom.:

348

AF XY:

0.0889

AC XY:

31232

AN XY:

351418

show subpopulations

African (AFR)

AF:

0.114

AC:

2030

AN:

17818

American (AMR)

AF:

0.0735

AC:

814

AN:

11074

Ashkenazi Jewish (ASJ)

AF:

0.0727

AC:

727

AN:

10000

East Asian (EAS)

AF:

0.0639

AC:

486

AN:

7610

South Asian (SAS)

AF:

0.0699

AC:

3274

AN:

46832

European-Finnish (FIN)

AF:

0.0500

AC:

542

AN:

10844

Middle Eastern (MID)

AF:

0.0695

AC:

129

AN:

1856

European-Non Finnish (NFE)

AF:

0.0925

AC:

53618

AN:

579430

Other (OTH)

AF:

0.0874

AC:

2338

AN:

26736

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

2410

4820

7229

9639

12049

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2430

4860

7290

9720

12150

<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:

0.0340

AC:

2265

AN:

66644

Hom.:

Cov.:

AF XY:

0.0361

AC XY:

1063

AN XY:

29458

show subpopulations

African (AFR)

AF:

0.112

AC:

2054

AN:

18258

American (AMR)

AF:

0.0184

AC:

AN:

4786

Ashkenazi Jewish (ASJ)

AF:

0.000467

AC:

AN:

2142

East Asian (EAS)

AF:

0.0256

AC:

AN:

1404

South Asian (SAS)

AF:

0.00382

AC:

AN:

1308

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1126

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00160

AC:

AN:

36228

Other (OTH)

AF:

0.0268

AC:

AN:

858

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.447

Heterozygous variant carriers

148

223

297

371

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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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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