Genetic Variant HMBS:c.33+124_33+135dupTTTTTTTTTTTT (chr11-119085172-C-CTTTTTTTTTTTT) – 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+124_33+135dupTTTTTTTTTTTT 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 0.0046 ( 44 hom., cov: 0)

Exomes 𝑓: 0.0028 ( 86 hom. )

Failed GnomAD Quality Control

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 sas. GnomAd4 allele frequency = 0.00463 (309/66782) while in subpopulation SAS AF = 0.00841 (11/1308). AF 95% confidence interval is 0.00583. There are 44 homozygotes in GnomAd4. There are 135 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High AC in GnomAd4 at 309 SD,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMBS	NM_000190.4 link	c.33+124_33+135dupTTTTTTTTTTTT		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+107insTTTTTTTTTTTT		intron_variant	Intron 1 of 13		NM_000190.4	ENSP00000498786.1		P08397-1

Frequencies

GnomAD3 genomes

AF:

0.00463

AC:

309

AN:

66746

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00147

Gnomad AMI

AF:

0.0109

Gnomad AMR

AF:

0.00313

Gnomad ASJ

AF:

0.00327

Gnomad EAS

AF:

0.00285

Gnomad SAS

AF:

0.00838

Gnomad FIN

AF:

0.000891

Gnomad MID

AF:

0.0125

Gnomad NFE

AF:

0.00652

Gnomad OTH

AF:

0.00235

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00277

AC:

2029

AN:

732450

Hom.:

Cov.:

AF XY:

0.00294

AC XY:

1064

AN XY:

362270

show subpopulations

African (AFR)

AF:

0.000707

AC:

AN:

18382

American (AMR)

AF:

0.00195

AC:

AN:

11816

Ashkenazi Jewish (ASJ)

AF:

0.00212

AC:

AN:

10368

East Asian (EAS)

AF:

0.00397

AC:

AN:

7814

South Asian (SAS)

AF:

0.00577

AC:

289

AN:

50098

European-Finnish (FIN)

AF:

0.00405

AC:

AN:

11354

Middle Eastern (MID)

AF:

0.00208

AC:

AN:

1920

European-Non Finnish (NFE)

AF:

0.00258

AC:

1531

AN:

593100

Other (OTH)

AF:

0.00254

AC:

AN:

27598

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

117

175

234

292

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

198

264

330

<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:

0.00463

AC:

309

AN:

66782

Hom.:

Cov.:

AF XY:

0.00457

AC XY:

135

AN XY:

29524

show subpopulations

African (AFR)

AF:

0.00147

AC:

AN:

18398

American (AMR)

AF:

0.00313

AC:

AN:

4794

Ashkenazi Jewish (ASJ)

AF:

0.00327

AC:

AN:

2142

East Asian (EAS)

AF:

0.00285

AC:

AN:

1404

South Asian (SAS)

AF:

0.00841

AC:

AN:

1308

European-Finnish (FIN)

AF:

0.000891

AC:

AN:

1122

Middle Eastern (MID)

AF:

0.0135

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00652

AC:

236

AN:

36222

Other (OTH)

AF:

0.00233

AC:

AN:

858

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.609

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-CTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT

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