Genetic Variant NM_000190.4:c.33+126_33+135dupTTTTTTTTTT (chr11-119085172-C-CTTTTTTTTTT) – 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+126_33+135dupTTTTTTTTTT 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 0.0071 ( 78 hom., cov: 0)

Exomes 𝑓: 0.0064 ( 268 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:

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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 = 0.00707 (472/66788) while in subpopulation EAS AF = 0.0321 (45/1402). AF 95% confidence interval is 0.0247. There are 78 homozygotes in GnomAd4. There are 183 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High AC in GnomAd4 at 472 SD,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMBS	NM_000190.4 link	c.33+126_33+135dupTTTTTTTTTT		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+107insTTTTTTTTTT		intron_variant	Intron 1 of 13		NM_000190.4	ENSP00000498786.1		P08397-1

Frequencies

GnomAD3 genomes

AF:

0.00707

AC:

472

AN:

66752

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00218

Gnomad AMI

AF:

0.00435

Gnomad AMR

AF:

0.00480

Gnomad ASJ

AF:

0.00561

Gnomad EAS

AF:

0.0321

Gnomad SAS

AF:

0.0122

Gnomad FIN

AF:

0.00624

Gnomad MID

AF:

0.0375

Gnomad NFE

AF:

0.00880

Gnomad OTH

AF:

0.00587

GnomAD4 exome

AF:

0.00640

AC:

4687

AN:

732004

Hom.:

268

Cov.:

AF XY:

0.00653

AC XY:

2363

AN XY:

362054

show subpopulations

African (AFR)

AF:

0.00190

AC:

AN:

18378

American (AMR)

AF:

0.00559

AC:

AN:

11812

Ashkenazi Jewish (ASJ)

AF:

0.00482

AC:

AN:

10364

East Asian (EAS)

AF:

0.0136

AC:

106

AN:

7812

South Asian (SAS)

AF:

0.00955

AC:

478

AN:

50076

European-Finnish (FIN)

AF:

0.00678

AC:

AN:

11352

Middle Eastern (MID)

AF:

0.00626

AC:

AN:

1918

European-Non Finnish (NFE)

AF:

0.00620

AC:

3676

AN:

592708

Other (OTH)

AF:

0.00678

AC:

187

AN:

27584

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

120

240

361

481

601

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

156

312

468

624

780

<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:

0.00707

AC:

472

AN:

66788

Hom.:

Cov.:

AF XY:

0.00620

AC XY:

183

AN XY:

29532

show subpopulations

African (AFR)

AF:

0.00217

AC:

AN:

18400

American (AMR)

AF:

0.00480

AC:

AN:

4796

Ashkenazi Jewish (ASJ)

AF:

0.00561

AC:

AN:

2140

East Asian (EAS)

AF:

0.0321

AC:

AN:

1402

South Asian (SAS)

AF:

0.0122

AC:

AN:

1308

European-Finnish (FIN)

AF:

0.00624

AC:

AN:

1122

Middle Eastern (MID)

AF:

0.0405

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00881

AC:

319

AN:

36228

Other (OTH)

AF:

0.00583

AC:

AN:

858

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.603

Heterozygous variant carriers

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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.50

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