Genetic Variant HMBS:c.33+132_33+135dupTTTT (chr11-119085172-C-CTTTT) – 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+132_33+135dupTTTT 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 0.00030 ( 3 hom., cov: 0)

Exomes 𝑓: 0.011 ( 450 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 = 0.000299 (20/66804) while in subpopulation EAS AF = 0.00142 (2/1404). AF 95% confidence interval is 0.000252. There are 3 homozygotes in GnomAd4. There are 5 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High AC in GnomAd4 at 20 SD,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMBS	NM_000190.4 link	c.33+132_33+135dupTTTT		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+107insTTTT		intron_variant	Intron 1 of 13		NM_000190.4	ENSP00000498786.1		P08397-1

Frequencies

GnomAD3 genomes

AF:

0.000300

AC:

AN:

66768

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000327

Gnomad AMI

AF:

0.00217

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00143

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000304

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0107

AC:

7791

AN:

730332

Hom.:

450

Cov.:

AF XY:

0.0111

AC XY:

4008

AN XY:

361148

show subpopulations

African (AFR)

AF:

0.00256

AC:

AN:

18368

American (AMR)

AF:

0.0101

AC:

119

AN:

11790

Ashkenazi Jewish (ASJ)

AF:

0.00832

AC:

AN:

10340

East Asian (EAS)

AF:

0.0299

AC:

232

AN:

7772

South Asian (SAS)

AF:

0.0144

AC:

719

AN:

49850

European-Finnish (FIN)

AF:

0.0158

AC:

178

AN:

11268

Middle Eastern (MID)

AF:

0.00836

AC:

AN:

1914

European-Non Finnish (NFE)

AF:

0.0103

AC:

6083

AN:

591506

Other (OTH)

AF:

0.0113

AC:

311

AN:

27524

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.428

Heterozygous variant carriers

243

487

730

974

1217

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

216

432

648

864

1080

<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:

0.000299

AC:

AN:

66804

Hom.:

Cov.:

AF XY:

0.000169

AC XY:

AN XY:

29540

show subpopulations

African (AFR)

AF:

0.000326

AC:

AN:

18402

American (AMR)

AF:

0.00

AC:

AN:

4796

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2142

East Asian (EAS)

AF:

0.00142

AC:

AN:

1404

South Asian (SAS)

AF:

0.00

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:

0.000304

AC:

AN:

36234

Other (OTH)

AF:

0.00

AC:

AN:

858

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.557

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

Alfa

AF:

0.00

Hom.:

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-CTTTTTTTTTTTTTTTTTTTTTTTTTT

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