Genetic Variant HMBS:c.33+117_33+135delTTTTTTTTTTTTTTTTTTT (chr11-119085172-CTTTTTTTTTTTTTTTTTTT-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+117_33+135delTTTTTTTTTTTTTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000188 in 799,598 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000015 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000019 ( 0 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: AD, SD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

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 GnomAdExome4 at 14 SD,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000190.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HMBS	NM_000190.4	MANE Select	c.33+117_33+135delTTTTTTTTTTTTTTTTTTT	intron	N/A	NP_000181.2
HMBS	NM_001425056.1		c.33+117_33+135delTTTTTTTTTTTTTTTTTTT	intron	N/A	NP_001411985.1
HMBS	NM_001425057.1		c.33+117_33+135delTTTTTTTTTTTTTTTTTTT	intron	N/A	NP_001411986.1	A0A3F2YNY7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HMBS	ENST00000652429.1	MANE Select	c.33+107_33+125delTTTTTTTTTTTTTTTTTTT	intron	N/A	ENSP00000498786.1	P08397-1
HMBS	ENST00000545621.5	TSL:1	n.33+107_33+125delTTTTTTTTTTTTTTTTTTT	intron	N/A	ENSP00000444849.1	F5H4X2
HMBS	ENST00000545901.5	TSL:1	n.186+107_186+125delTTTTTTTTTTTTTTTTTTT	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0000150

AC:

AN:

66768

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000762

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000191

AC:

AN:

732830

Hom.:

AF XY:

0.0000248

AC XY:

AN XY:

362474

show subpopulations

African (AFR)

AF:

0.00

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:

0.000199

AC:

AN:

50144

European-Finnish (FIN)

AF:

0.0000880

AC:

AN:

11370

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1920

European-Non Finnish (NFE)

AF:

0.00000506

AC:

AN:

593390

Other (OTH)

AF:

0.00

AC:

AN:

27608

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

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:

0.0000150

AC:

AN:

66768

Hom.:

Cov.:

AF XY:

0.0000339

AC XY:

AN XY:

29496

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

18368

American (AMR)

AF:

0.00

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:

0.000762

AC:

AN:

1312

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1126

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

36236

Other (OTH)

AF:

0.00

AC:

AN:

852

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.725

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 v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.8

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over