dbSNP rs2290647: GRAMD1A:p.Ala357Ala (chr19-35015825-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_020895.5(GRAMD1A):c.1071G>A(p.Ala357Ala) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.3 in 1,612,494 control chromosomes in the GnomAD database, including 75,002 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.30 ( 7151 hom., cov: 32)

Exomes 𝑓: 0.30 ( 67851 hom. )

Consequence

GRAMD1A
NM_020895.5 splice_region, synonymous

Scores

Splicing: ADA: 0.00002610

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.737

Publications

29 publications found

Variant links:

Genes affected

GRAMD1A (HGNC:29305): (GRAM domain containing 1A) Predicted to enable cholesterol binding activity and cholesterol transfer activity. Predicted to be involved in cellular response to cholesterol. Located in cytosol; organelle membrane contact site; and plasma membrane. Is extrinsic component of cytoplasmic side of plasma membrane and intrinsic component of endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

GRAMD1A links:

ENSG00000271032 (HGNC:):

ENSG00000271032 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.319 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRAMD1A	NM_020895.5 link	c.1071G>A	p.Ala357Ala	splice_region_variant, synonymous_variant	Exon 11 of 20	ENST00000317991.10	NP_065946.2	Q96CP6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRAMD1A	ENST00000317991.10 link	c.1071G>A	p.Ala357Ala	splice_region_variant, synonymous_variant	Exon 11 of 20	1	NM_020895.5	ENSP00000441032.1		Q96CP6-1

Frequencies

GnomAD3 genomes

AF:

0.304

AC:

46135

AN:

151958

Hom.:

7154

Cov.:

show subpopulations

Gnomad AFR

AF:

0.273

Gnomad AMI

AF:

0.366

Gnomad AMR

AF:

0.299

Gnomad ASJ

AF:

0.471

Gnomad EAS

AF:

0.234

Gnomad SAS

AF:

0.178

Gnomad FIN

AF:

0.327

Gnomad MID

AF:

0.434

Gnomad NFE

AF:

0.322

Gnomad OTH

AF:

0.353

GnomAD2 exomes

AF:

0.288

AC:

71233

AN:

247532

AF XY:

0.288

show subpopulations

Gnomad AFR exome

AF:

0.273

Gnomad AMR exome

AF:

0.223

Gnomad ASJ exome

AF:

0.460

Gnomad EAS exome

AF:

0.245

Gnomad FIN exome

AF:

0.323

Gnomad NFE exome

AF:

0.322

Gnomad OTH exome

AF:

0.332

GnomAD4 exome

AF:

0.300

AC:

438100

AN:

1460418

Hom.:

67851

Cov.:

AF XY:

0.298

AC XY:

216804

AN XY:

726524

show subpopulations

African (AFR)

AF:

0.280

AC:

9381

AN:

33452

American (AMR)

AF:

0.232

AC:

10339

AN:

44620

Ashkenazi Jewish (ASJ)

AF:

0.463

AC:

12078

AN:

26076

East Asian (EAS)

AF:

0.241

AC:

9552

AN:

39650

South Asian (SAS)

AF:

0.184

AC:

15831

AN:

86178

European-Finnish (FIN)

AF:

0.316

AC:

16843

AN:

53226

Middle Eastern (MID)

AF:

0.457

AC:

2634

AN:

5758

European-Non Finnish (NFE)

AF:

0.308

AC:

342455

AN:

1111120

Other (OTH)

AF:

0.315

AC:

18987

AN:

60338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

14570

29140

43710

58280

72850

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10926

21852

32778

43704

54630

<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:

0.303

AC:

46127

AN:

152076

Hom.:

7151

Cov.:

AF XY:

0.302

AC XY:

22463

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.272

AC:

11287

AN:

41458

American (AMR)

AF:

0.299

AC:

4567

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.471

AC:

1634

AN:

3470

East Asian (EAS)

AF:

0.234

AC:

1213

AN:

5178

South Asian (SAS)

AF:

0.178

AC:

857

AN:

4828

European-Finnish (FIN)

AF:

0.327

AC:

3463

AN:

10586

Middle Eastern (MID)

AF:

0.435

AC:

128

AN:

294

European-Non Finnish (NFE)

AF:

0.322

AC:

21902

AN:

67958

Other (OTH)

AF:

0.351

AC:

742

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1689

3378

5068

6757

8446

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

454

908

1362

1816

2270

<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:

0.320

Hom.:

36111

Bravo

AF:

0.303

Asia WGS

AF:

0.195

AC:

677

AN:

3478

EpiCase

AF:

0.347

EpiControl

AF:

0.347

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

(source)

DANN

Benign

0.91

PhyloP100

-0.74

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=74/26

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000026

dbscSNV1_RF

Benign

0.0020

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.99

Position offset: 2

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