Genetic Variant HMBS:c.33+123_33+135dupTTTTTTTTTTTTT (chr11-119085172-C-CTTTTTTTTTTTTT) – 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+123_33+135dupTTTTTTTTTTTTT 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 0.0017 ( 13 hom., cov: 0)

Exomes 𝑓: 0.0015 ( 51 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 = 0.00168 (112/66792) while in subpopulation EAS AF = 0.00641 (9/1404). AF 95% confidence interval is 0.00334. There are 13 homozygotes in GnomAd4. There are 51 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High AC in GnomAd4 at 112 SD,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMBS	NM_000190.4 link	c.33+123_33+135dupTTTTTTTTTTTTT		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+107insTTTTTTTTTTTTT		intron_variant	Intron 1 of 13		NM_000190.4	ENSP00000498786.1		P08397-1

Frequencies

GnomAD3 genomes

AF:

0.00168

AC:

112

AN:

66756

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000871

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00104

Gnomad ASJ

AF:

0.00233

Gnomad EAS

AF:

0.00642

Gnomad SAS

AF:

0.00152

Gnomad FIN

AF:

0.000890

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00204

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00152

AC:

1114

AN:

732636

Hom.:

Cov.:

AF XY:

0.00163

AC XY:

589

AN XY:

362388

show subpopulations

African (AFR)

AF:

0.000490

AC:

AN:

18384

American (AMR)

AF:

0.00161

AC:

AN:

11818

Ashkenazi Jewish (ASJ)

AF:

0.000771

AC:

AN:

10370

East Asian (EAS)

AF:

0.00281

AC:

AN:

7824

South Asian (SAS)

AF:

0.00291

AC:

146

AN:

50120

European-Finnish (FIN)

AF:

0.00123

AC:

AN:

11364

Middle Eastern (MID)

AF:

0.000521

AC:

AN:

1920

European-Non Finnish (NFE)

AF:

0.00143

AC:

846

AN:

593236

Other (OTH)

AF:

0.00178

AC:

AN:

27600

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

129

161

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<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:

0.00168

AC:

112

AN:

66792

Hom.:

Cov.:

AF XY:

0.00173

AC XY:

AN XY:

29536

show subpopulations

African (AFR)

AF:

0.000870

AC:

AN:

18400

American (AMR)

AF:

0.00104

AC:

AN:

4794

Ashkenazi Jewish (ASJ)

AF:

0.00233

AC:

AN:

2142

East Asian (EAS)

AF:

0.00641

AC:

AN:

1404

South Asian (SAS)

AF:

0.00153

AC:

AN:

1308

European-Finnish (FIN)

AF:

0.000890

AC:

AN:

1124

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00204

AC:

AN:

36228

Other (OTH)

AF:

0.00

AC:

AN:

858

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.623

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-CTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT

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