19-35015825-G-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_001320036.2(GRAMD1A):​c.1331-2G>C variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 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: not found (cov: 32)
• Consequence: GRAMD1A NM_001320036.2 splice_acceptor, intron
• Scores: Splicing: ADA: 0.00002801
• 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: Uncertain_significance. The variant received 4 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 8.3, offset of -3, new splice context is: cggctctcctctgtctccAGccg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage

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>C	p.Ala357Ala	splice_region synonymous	Exon 11 of 20	NP_065946.2	Q96CP6-1
	GRAMD1A	NM_001320034.2		c.1071G>C	p.Ala357Ala	splice_region synonymous	Exon 11 of 19	NP_001306963.1	Q96CP6-3
	GRAMD1A	NM_001136199.3		c.1050G>C	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>C	p.Ala357Ala	splice_region synonymous	Exon 11 of 20	ENSP00000441032.1	Q96CP6-1
	GRAMD1A	ENST00000598118.1	TSL:1	n.857G>C		non_coding_transcript_exon	Exon 1 of 9
	GRAMD1A	ENST00000942872.1		c.608G>C	p.Arg203Pro	missense splice_region	Exon 8 of 15	ENSP00000612931.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.50
DANN	Benign	0.68
PhyloP100		-0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000028
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs2290647; hg19: chr19-35506729;