10-43198061-G-C

Variant names:

• chr10-43198061-G-C
• NM_145313.4:c.1167C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_145313.4(RASGEF1A):​c.1167C>G​(p.Ile389Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RASGEF1A NM_145313.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.21

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RASGEF1A	NM_145313.4	c.1167C>G	p.Ile389Met	missense_variant	Exon 10 of 13	ENST00000395810.6	NP_660356.2
RASGEF1A	NM_001282862.2	c.1191C>G	p.Ile397Met	missense_variant	Exon 10 of 13		NP_001269791.1
RASGEF1A	XM_005271809.4	c.927C>G	p.Ile309Met	missense_variant	Exon 9 of 12		XP_005271866.1
RASGEF1A	XM_011539500.3	c.927C>G	p.Ile309Met	missense_variant	Exon 9 of 12		XP_011537802.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RASGEF1A	ENST00000395810.6	c.1167C>G	p.Ile389Met	missense_variant	Exon 10 of 13	1	NM_145313.4	ENSP00000379155.1
RASGEF1A	ENST00000374459.5	c.1191C>G	p.Ile397Met	missense_variant	Exon 10 of 13	2		ENSP00000363583.1
RASGEF1A	ENST00000395809.5	c.1167C>G	p.Ile389Met	missense_variant	Exon 10 of 13	2		ENSP00000379154.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1167C>G (p.I389M) alteration is located in exon 9 (coding exon 9) of the RASGEF1A gene. This alteration results from a C to G substitution at nucleotide position 1167, causing the isoleucine (I) at amino acid position 389 to be replaced by a methionine (M). 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	Benign	0.15
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.028	.;T;T
Eigen	Benign	0.15
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.90	D;.;D
M_CAP	Benign	0.0084	T
MetaRNN	Uncertain	0.62	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	.;L;L
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Benign	0.22
Sift	Uncertain	0.0050	D;D;D
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		0.85	P;P;P
Vest4		0.66
MutPred		0.47		.;Loss of catalytic residue at I389 (P = 0.0296);Loss of catalytic residue at I389 (P = 0.0296);
MVP		0.34
MPC		1.6
ClinPred		0.84	D
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.42
gMVP		0.81

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: chr10-43693509;