10-43200229-C-T

Variant names:

• chr10-43200229-C-T
• rs1426796485
• NM_145313.4:c.709G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_145313.4(RASGEF1A):​c.709G>A​(p.Asp237Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 34)
• Consequence: RASGEF1A NM_145313.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.49

Genes affected

RASGEF1A (HGNC:24246): (RasGEF domain family member 1A) Enables guanyl-nucleotide exchange factor activity. Involved in cell migration and positive regulation of Ras protein signal transduction. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.821

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RASGEF1A	NM_145313.4	c.709G>A	p.Asp237Asn	missense_variant	Exon 6 of 13	ENST00000395810.6	NP_660356.2
RASGEF1A	NM_001282862.2	c.733G>A	p.Asp245Asn	missense_variant	Exon 6 of 13		NP_001269791.1
RASGEF1A	XM_005271809.4	c.469G>A	p.Asp157Asn	missense_variant	Exon 5 of 12		XP_005271866.1
RASGEF1A	XM_011539500.3	c.469G>A	p.Asp157Asn	missense_variant	Exon 5 of 12		XP_011537802.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RASGEF1A	ENST00000395810.6	c.709G>A	p.Asp237Asn	missense_variant	Exon 6 of 13	1	NM_145313.4	ENSP00000379155.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 21, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.709G>A (p.D237N) alteration is located in exon 5 (coding exon 5) of the RASGEF1A gene. This alteration results from a G to A substitution at nucleotide position 709, causing the aspartic acid (D) at amino acid position 237 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Benign	-0.37
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.18	.;T;T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D;.;D
M_CAP	Benign	0.015	T
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.0	.;M;M
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.2	N;N;N
REVEL	Benign	0.27
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		0.94	P;P;P
Vest4		0.56
MutPred		0.78		.;Loss of phosphorylation at S232 (P = 0.1136);Loss of phosphorylation at S232 (P = 0.1136);
MVP		0.34
MPC		1.0
ClinPred		0.91	D
GERP RS		5.3
Varity_R		0.45
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs1426796485; hg19: chr10-43695677; COSMIC: COSV100988695;