Genetic Variant HMBS:c.33+122_33+135delTTTTTTTTTTTTTT (chr11-119085172-CTTTTTTTTTTTTTT-C) – 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+135delTTTTTTTTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00955 in 797,442 control chromosomes in the GnomAD database, including 7 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_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 0.00040 ( 1 hom., cov: 0)

Exomes 𝑓: 0.010 ( 6 hom. )

Consequence

HMBS
NM_000190.4 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.83

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 = 0.000404 (27/66796) while in subpopulation SAS AF = 0.00382 (5/1308). AF 95% confidence interval is 0.00151. There are 1 homozygotes in GnomAd4. There are 10 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High AC in GnomAd4 at 27 SD,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMBS	NM_000190.4 link	c.33+122_33+135delTTTTTTTTTTTTTT		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+107_33+120delTTTTTTTTTTTTTT		intron_variant	Intron 1 of 13		NM_000190.4	ENSP00000498786.1		P08397-1

Frequencies

GnomAD3 genomes

AF:

0.000419

AC:

AN:

66760

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000544

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000418

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000713

Gnomad SAS

AF:

0.00381

Gnomad FIN

AF:

0.00266

Gnomad MID

AF:

0.0125

Gnomad NFE

AF:

0.000386

Gnomad OTH

AF:

0.00117

GnomAD4 exome

AF:

0.0104

AC:

7590

AN:

730646

Hom.:

AF XY:

0.0105

AC XY:

3789

AN XY:

361292

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00305

AC:

AN:

18348

American (AMR)

AF:

0.00602

AC:

AN:

11792

Ashkenazi Jewish (ASJ)

AF:

0.0265

AC:

273

AN:

10298

East Asian (EAS)

AF:

0.00102

AC:

AN:

7820

South Asian (SAS)

AF:

0.00912

AC:

455

AN:

49894

European-Finnish (FIN)

AF:

0.0251

AC:

284

AN:

11294

Middle Eastern (MID)

AF:

0.0157

AC:

AN:

1916

European-Non Finnish (NFE)

AF:

0.0103

AC:

6102

AN:

591770

Other (OTH)

AF:

0.0113

AC:

311

AN:

27514

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.354

Heterozygous variant carriers

395

790

1184

1579

1974

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

182

364

546

728

910

<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:

0.000404

AC:

AN:

66796

Hom.:

Cov.:

AF XY:

0.000339

AC XY:

AN XY:

29536

show subpopulations

African (AFR)

AF:

0.0000543

AC:

AN:

18402

American (AMR)

AF:

0.000417

AC:

AN:

4796

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2140

East Asian (EAS)

AF:

0.000712

AC:

AN:

1404

South Asian (SAS)

AF:

0.00382

AC:

AN:

1308

European-Finnish (FIN)

AF:

0.00266

AC:

AN:

1126

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000386

AC:

AN:

36228

Other (OTH)

AF:

0.00117

AC:

AN:

858

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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

1.8

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