dbSNP rs686624: HMBS:c.-235T>A (chr11-119084799-T-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000190.4(HMBS):c.-235T>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.834 in 612,592 control chromosomes in the GnomAD database, including 214,187 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.83 ( 52913 hom., cov: 33)

Exomes 𝑓: 0.83 ( 161274 hom. )

Consequence

HMBS
NM_000190.4 upstream_gene

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.630

Publications

12 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 11-119084799-T-A is Benign according to our data. Variant chr11-119084799-T-A is described in ClinVar as Benign. ClinVar VariationId is 255484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.907 is higher than 0.05.

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.-235T>A	upstream_gene	N/A	NP_000181.2
HMBS	NM_001425056.1		c.-235T>A	upstream_gene	N/A	NP_001411985.1
HMBS	NM_001425057.1		c.-235T>A	upstream_gene	N/A	NP_001411986.1	A0A3F2YNY7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HMBS	ENST00000652429.1	MANE Select	c.-235T>A	upstream_gene	N/A	ENSP00000498786.1	P08397-1
HMBS	ENST00000545621.5	TSL:1	n.-235T>A	upstream_gene	N/A	ENSP00000444849.1	F5H4X2
HMBS	ENST00000545901.5	TSL:1	n.-82T>A	upstream_gene	N/A

Frequencies

GnomAD3 genomes

AF:

0.831

AC:

126450

AN:

152112

Hom.:

52879

Cov.:

show subpopulations

Gnomad AFR

AF:

0.864

Gnomad AMI

AF:

0.755

Gnomad AMR

AF:

0.690

Gnomad ASJ

AF:

0.829

Gnomad EAS

AF:

0.929

Gnomad SAS

AF:

0.879

Gnomad FIN

AF:

0.819

Gnomad MID

AF:

0.839

Gnomad NFE

AF:

0.835

Gnomad OTH

AF:

0.837

GnomAD4 exome

AF:

0.835

AC:

384304

AN:

460362

Hom.:

161274

AF XY:

0.837

AC XY:

204931

AN XY:

244712

show subpopulations

African (AFR)

AF:

0.864

AC:

11098

AN:

12846

American (AMR)

AF:

0.613

AC:

12940

AN:

21094

Ashkenazi Jewish (ASJ)

AF:

0.837

AC:

11781

AN:

14080

East Asian (EAS)

AF:

0.926

AC:

28813

AN:

31112

South Asian (SAS)

AF:

0.869

AC:

41744

AN:

48024

European-Finnish (FIN)

AF:

0.815

AC:

23964

AN:

29406

Middle Eastern (MID)

AF:

0.812

AC:

1665

AN:

2050

European-Non Finnish (NFE)

AF:

0.837

AC:

230333

AN:

275286

Other (OTH)

AF:

0.830

AC:

21966

AN:

26464

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

3156

6313

9469

12626

15782

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

908

1816

2724

3632

4540

<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:

0.831

AC:

126535

AN:

152230

Hom.:

52913

Cov.:

AF XY:

0.829

AC XY:

61708

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.863

AC:

35866

AN:

41536

American (AMR)

AF:

0.689

AC:

10531

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.829

AC:

2876

AN:

3470

East Asian (EAS)

AF:

0.929

AC:

4816

AN:

5186

South Asian (SAS)

AF:

0.879

AC:

4244

AN:

4830

European-Finnish (FIN)

AF:

0.819

AC:

8686

AN:

10606

Middle Eastern (MID)

AF:

0.837

AC:

246

AN:

294

European-Non Finnish (NFE)

AF:

0.835

AC:

56810

AN:

68000

Other (OTH)

AF:

0.839

AC:

1773

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1084

2169

3253

4338

5422

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

888

1776

2664

3552

4440

<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:

0.827

Hom.:

6508

Bravo

AF:

0.819

Asia WGS

AF:

0.900

AC:

3129

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

3.6

(source)

DANN

Benign

0.42

PhyloP100

-0.63

PromoterAI

0.16

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over