Genetic Variant HMBS:c.33+114_33+135delTTTTTTTTTTTTTTTTTTTTTT (chr11-119085172-CTTTTTTTTTTTTTTTTTTTTTT-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000190.4(HMBS):c.33+114_33+135delTTTTTTTTTTTTTTTTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000158 in 799,600 control chromosomes in the GnomAD database, including 1 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 0.00021 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00015 ( 1 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: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 14 SD,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMBS	NM_000190.4 link	c.33+114_33+135delTTTTTTTTTTTTTTTTTTTTTT		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+128delTTTTTTTTTTTTTTTTTTTTTT		intron_variant	Intron 1 of 13		NM_000190.4	ENSP00000498786.1		P08397-1

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

66768

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000109

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000209

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000888

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000276

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000153

AC:

112

AN:

732832

Hom.:

AF XY:

0.000124

AC XY:

AN XY:

362476

show subpopulations

African (AFR)

AF:

0.000163

AC:

AN:

18384

American (AMR)

AF:

0.00

AC:

AN:

11818

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

10372

East Asian (EAS)

AF:

0.00

AC:

AN:

7824

South Asian (SAS)

AF:

0.00

AC:

AN:

50144

European-Finnish (FIN)

AF:

0.000176

AC:

AN:

11370

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1920

European-Non Finnish (NFE)

AF:

0.000170

AC:

101

AN:

593392

Other (OTH)

AF:

0.000217

AC:

AN:

27608

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.588

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000210

AC:

AN:

66768

Hom.:

Cov.:

AF XY:

0.000305

AC XY:

AN XY:

29496

show subpopulations

African (AFR)

AF:

0.000109

AC:

AN:

18368

American (AMR)

AF:

0.000209

AC:

AN:

4790

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2142

East Asian (EAS)

AF:

0.00

AC:

AN:

1402

South Asian (SAS)

AF:

0.00

AC:

AN:

1312

European-Finnish (FIN)

AF:

0.000888

AC:

AN:

1126

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000276

AC:

AN:

36236

Other (OTH)

AF:

0.00

AC:

AN:

852

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.771

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

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