rs2290647

Variant names:

• chr19-35015825-G-A
• rs2290647
• NM_020895.5:c.1071G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-35015825-G-A
• chr19-35015825-G-C
• chr19-35015825-G-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PVS1_Moderate BA1

The NM_001320036.2(GRAMD1A):​c.1331-2G>A variant causes a splice acceptor, intron 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. Variant has been reported in ClinVar as (no stars).

• Frequency:
  • Genomes: 𝑓 0.30 (7151 hom., cov: 32)
  • Exomes 𝑓: 0.30 (67851 hom.)
• Consequence: GRAMD1A NM_001320036.2 splice_acceptor, intron
• Scores: Splicing: ADA: 0.00002610
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.737
• Publications: 29 publications found

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]

ENSG00000271032 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.058240395 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8.4, offset of 0 (no position change), new splice context is: ctctcctctgtctccagcAGact. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.319 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001320036.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRAMD1A	NM_020895.5	MANE Select	c.1071G>A	p.Ala357Ala	splice_region synonymous	Exon 11 of 20	NP_065946.2	Q96CP6-1
	GRAMD1A	NM_001320034.2		c.1071G>A	p.Ala357Ala	splice_region synonymous	Exon 11 of 19	NP_001306963.1	Q96CP6-3
	GRAMD1A	NM_001136199.3		c.1050G>A	p.Ala350Ala	splice_region synonymous	Exon 10 of 18	NP_001129671.1	Q96CP6-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRAMD1A	ENST00000317991.10	TSL:1 MANE Select	c.1071G>A	p.Ala357Ala	splice_region synonymous	Exon 11 of 20	ENSP00000441032.1	Q96CP6-1
	GRAMD1A	ENST00000598118.1	TSL:1	n.857G>A		non_coding_transcript_exon	Exon 1 of 9
	GRAMD1A	ENST00000942872.1		c.608G>A	p.Arg203Gln	missense splice_region	Exon 8 of 15	ENSP00000612931.1

Frequencies

GnomAD3 genomes AF: 0.304 AC: 46135 AN: 151958 Hom.: 7154 Cov.: 32

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

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.: 34 AF XY: 0.298 AC XY: 216804 AN XY: 726524

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

GnomAD4 genome AF: 0.303 AC: 46127 AN: 152076 Hom.: 7151 Cov.: 32 AF XY: 0.302 AC XY: 22463 AN XY: 74336

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

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	17
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)

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

Other links and lift over

dbSNP: rs2290647; hg19: chr19-35506729; COSMIC: COSV58766860; COSMIC: COSV58766860;