Genetic Variant HMBS:c.33+122_33+135dupTTTTTTTTTTTTTT (chr11-119085172-C-CTTTTTTTTTTTTTT) – 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+122_33+135dupTTTTTTTTTTTTTT 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 0.00075 ( 9 hom., cov: 0)

Exomes 𝑓: 0.00084 ( 29 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 = 0.000748 (50/66804) while in subpopulation EAS AF = 0.00427 (6/1404). AF 95% confidence interval is 0.00186. There are 9 homozygotes in GnomAd4. There are 25 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High AC in GnomAd4 at 50 SD,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMBS	NM_000190.4 link	c.33+122_33+135dupTTTTTTTTTTTTTT		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+107insTTTTTTTTTTTTTT		intron_variant	Intron 1 of 13		NM_000190.4	ENSP00000498786.1		P08397-1

Frequencies

GnomAD3 genomes

AF:

0.000749

AC:

AN:

66768

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000109

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00140

Gnomad EAS

AF:

0.00428

Gnomad SAS

AF:

0.00305

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000938

Gnomad OTH

AF:

0.00117

GnomAD4 exome

AF:

0.000845

AC:

619

AN:

732704

Hom.:

Cov.:

AF XY:

0.000891

AC XY:

323

AN XY:

362418

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

18380

American (AMR)

AF:

0.000677

AC:

AN:

11818

Ashkenazi Jewish (ASJ)

AF:

0.000675

AC:

AN:

10370

East Asian (EAS)

AF:

0.00217

AC:

AN:

7820

South Asian (SAS)

AF:

0.00168

AC:

AN:

50120

European-Finnish (FIN)

AF:

0.00167

AC:

AN:

11366

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1920

European-Non Finnish (NFE)

AF:

0.000782

AC:

464

AN:

593302

Other (OTH)

AF:

0.000724

AC:

AN:

27608

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000748

AC:

AN:

66804

Hom.:

Cov.:

AF XY:

0.000846

AC XY:

AN XY:

29540

show subpopulations

African (AFR)

AF:

0.000109

AC:

AN:

18402

American (AMR)

AF:

0.00

AC:

AN:

4796

Ashkenazi Jewish (ASJ)

AF:

0.00140

AC:

AN:

2142

East Asian (EAS)

AF:

0.00427

AC:

AN:

1404

South Asian (SAS)

AF:

0.00306

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:

0.000938

AC:

AN:

36234

Other (OTH)

AF:

0.00117

AC:

AN:

858

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.645

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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11-119085172-CTTTTTTTTTTTTTTTTTTTTTT-CTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT

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