Genetic Variant NM_000190.4:c.33+128_33+135dupTTTTTTTT (chr11-119085172-C-CTTTTTTTT) – 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+128_33+135dupTTTTTTTT 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 0.040 ( 461 hom., cov: 0)

Exomes 𝑓: 0.015 ( 879 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.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0672 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMBS	NM_000190.4 link	c.33+128_33+135dupTTTTTTTT		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+107insTTTTTTTT		intron_variant	Intron 1 of 13		NM_000190.4	ENSP00000498786.1		P08397-1

Frequencies

GnomAD3 genomes

AF:

0.0402

AC:

2681

AN:

66682

Hom.:

461

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0138

Gnomad AMI

AF:

0.0870

Gnomad AMR

AF:

0.0310

Gnomad ASJ

AF:

0.0678

Gnomad EAS

AF:

0.0793

Gnomad SAS

AF:

0.0636

Gnomad FIN

AF:

0.0279

Gnomad MID

AF:

0.0750

Gnomad NFE

AF:

0.0507

Gnomad OTH

AF:

0.0341

GnomAD4 exome

AF:

0.0147

AC:

10735

AN:

731206

Hom.:

879

Cov.:

AF XY:

0.0152

AC XY:

5491

AN XY:

361660

show subpopulations

African (AFR)

AF:

0.00343

AC:

AN:

18372

American (AMR)

AF:

0.0101

AC:

119

AN:

11800

Ashkenazi Jewish (ASJ)

AF:

0.0103

AC:

107

AN:

10360

East Asian (EAS)

AF:

0.0282

AC:

220

AN:

7806

South Asian (SAS)

AF:

0.0230

AC:

1150

AN:

50058

European-Finnish (FIN)

AF:

0.0256

AC:

290

AN:

11342

Middle Eastern (MID)

AF:

0.0156

AC:

AN:

1918

European-Non Finnish (NFE)

AF:

0.0141

AC:

8346

AN:

592006

Other (OTH)

AF:

0.0149

AC:

410

AN:

27544

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

276

552

828

1104

1380

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

320

640

960

1280

1600

<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:

0.0402

AC:

2681

AN:

66718

Hom.:

461

Cov.:

AF XY:

0.0372

AC XY:

1098

AN XY:

29506

show subpopulations

African (AFR)

AF:

0.0138

AC:

254

AN:

18388

American (AMR)

AF:

0.0309

AC:

148

AN:

4784

Ashkenazi Jewish (ASJ)

AF:

0.0678

AC:

145

AN:

2140

East Asian (EAS)

AF:

0.0792

AC:

111

AN:

1402

South Asian (SAS)

AF:

0.0637

AC:

AN:

1302

European-Finnish (FIN)

AF:

0.0279

AC:

AN:

1112

Middle Eastern (MID)

AF:

0.0811

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0507

AC:

1834

AN:

36200

Other (OTH)

AF:

0.0339

AC:

AN:

856

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

112

169

225

281

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.0184

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

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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