10-43203338-C-A

Variant names:

• chr10-43203338-C-A
• NM_145313.4:c.281G>T

Variant summary

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

The NM_145313.4(RASGEF1A):​c.281G>T​(p.Cys94Phe) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RASGEF1A NM_145313.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.76

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, 0.814

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RASGEF1A	NM_145313.4	c.281G>T	p.Cys94Phe	missense_variant	Exon 3 of 13	ENST00000395810.6	NP_660356.2
RASGEF1A	NM_001282862.2	c.305G>T	p.Cys102Phe	missense_variant	Exon 3 of 13		NP_001269791.1
RASGEF1A	XM_005271809.4	c.41G>T	p.Cys14Phe	missense_variant	Exon 2 of 12		XP_005271866.1
RASGEF1A	XM_011539500.3	c.41G>T	p.Cys14Phe	missense_variant	Exon 2 of 12		XP_011537802.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RASGEF1A	ENST00000395810.6	c.281G>T	p.Cys94Phe	missense_variant	Exon 3 of 13	1	NM_145313.4	ENSP00000379155.1
RASGEF1A	ENST00000374459.5	c.305G>T	p.Cys102Phe	missense_variant	Exon 3 of 13	2		ENSP00000363583.1
RASGEF1A	ENST00000395809.5	c.281G>T	p.Cys94Phe	missense_variant	Exon 3 of 13	2		ENSP00000379154.1
RASGEF1A	ENST00000472864.1	n.291G>T		non_coding_transcript_exon_variant	Exon 2 of 5	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1426782 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 706490

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 21, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.281G>T (p.C94F) alteration is located in exon 2 (coding exon 2) of the RASGEF1A gene. This alteration results from a G to T substitution at nucleotide position 281, causing the cysteine (C) at amino acid position 94 to be replaced by a phenylalanine (F). 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	0.34
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.12	.;T;T
Eigen	Benign	-0.076
Eigen_PC	Benign	-0.023
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.80	T;.;T
M_CAP	Benign	0.052	D
MetaRNN	Pathogenic	0.81	D;D;D
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.7	.;M;M
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-7.0	D;D;D
REVEL	Uncertain	0.31
Sift	Benign	0.049	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		0.11	B;B;B
Vest4		0.80
MutPred		0.69		.;Gain of ubiquitination at K98 (P = 0.102);Gain of ubiquitination at K98 (P = 0.102);
MVP		0.73
MPC		1.2
ClinPred		0.93	D
GERP RS		3.5
Varity_R		0.65
gMVP		0.71

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-43698786;