Genetic Variant NM_000190.4:c.33+125_33+135dupTTTTTTTTTTT (chr11-119085172-C-CTTTTTTTTTTT) – 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+135dupTTTTTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_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 0.0059 ( 43 hom., cov: 0)

Exomes 𝑓: 0.0045 ( 176 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 = 0.0059 (394/66794) while in subpopulation EAS AF = 0.0171 (24/1404). AF 95% confidence interval is 0.0118. There are 43 homozygotes in GnomAd4. There are 162 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High AC in GnomAd4 at 394 SD,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMBS	NM_000190.4 link	c.33+125_33+135dupTTTTTTTTTTT		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+107insTTTTTTTTTTT		intron_variant	Intron 1 of 13		NM_000190.4	ENSP00000498786.1		P08397-1

Frequencies

GnomAD3 genomes

AF:

0.00590

AC:

394

AN:

66758

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00218

Gnomad AMI

AF:

0.00866

Gnomad AMR

AF:

0.00272

Gnomad ASJ

AF:

0.00654

Gnomad EAS

AF:

0.0171

Gnomad SAS

AF:

0.00686

Gnomad FIN

AF:

0.00178

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00787

Gnomad OTH

AF:

0.00353

GnomAD4 exome

AF:

0.00451

AC:

3300

AN:

732258

Hom.:

176

Cov.:

AF XY:

0.00469

AC XY:

1699

AN XY:

362166

show subpopulations

African (AFR)

AF:

0.00120

AC:

AN:

18382

American (AMR)

AF:

0.00313

AC:

AN:

11808

Ashkenazi Jewish (ASJ)

AF:

0.00328

AC:

AN:

10370

East Asian (EAS)

AF:

0.00627

AC:

AN:

7812

South Asian (SAS)

AF:

0.00739

AC:

370

AN:

50078

European-Finnish (FIN)

AF:

0.00511

AC:

AN:

11360

Middle Eastern (MID)

AF:

0.00417

AC:

AN:

1920

European-Non Finnish (NFE)

AF:

0.00441

AC:

2613

AN:

592940

Other (OTH)

AF:

0.00395

AC:

109

AN:

27588

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

164

246

328

410

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

106

212

318

424

530

<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:

0.00590

AC:

394

AN:

66794

Hom.:

Cov.:

AF XY:

0.00548

AC XY:

162

AN XY:

29536

show subpopulations

African (AFR)

AF:

0.00217

AC:

AN:

18402

American (AMR)

AF:

0.00271

AC:

AN:

4794

Ashkenazi Jewish (ASJ)

AF:

0.00654

AC:

AN:

2142

East Asian (EAS)

AF:

0.0171

AC:

AN:

1404

South Asian (SAS)

AF:

0.00688

AC:

AN:

1308

European-Finnish (FIN)

AF:

0.00178

AC:

AN:

1122

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00787

AC:

285

AN:

36230

Other (OTH)

AF:

0.00350

AC:

AN:

856

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