10-43200678-G-C

Position:

• chr10-43200678-G-C

Variant summary

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

The NM_145313.4(RASGEF1A):​c.670C>G​(p.His224Asp) 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: 33)
• Consequence: RASGEF1A NM_145313.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.43

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, 0.77

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RASGEF1A	NM_145313.4	c.670C>G	p.His224Asp	missense_variant	5/13	ENST00000395810.6	NP_660356.2
RASGEF1A	NM_001282862.2	c.694C>G	p.His232Asp	missense_variant	5/13		NP_001269791.1
RASGEF1A	XM_005271809.4	c.430C>G	p.His144Asp	missense_variant	4/12		XP_005271866.1
RASGEF1A	XM_011539500.3	c.430C>G	p.His144Asp	missense_variant	4/12		XP_011537802.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RASGEF1A	ENST00000395810.6	c.670C>G	p.His224Asp	missense_variant	5/13	1	NM_145313.4	ENSP00000379155	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 25, 2023

The c.670C>G (p.H224D) alteration is located in exon 4 (coding exon 4) of the RASGEF1A gene. This alteration results from a C to G substitution at nucleotide position 670, causing the histidine (H) at amino acid position 224 to be replaced by an aspartic acid (D). 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	Pathogenic	0.73
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	.;T;T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.97	D;.;D
M_CAP	Benign	0.019	T
MetaRNN	Pathogenic	0.77	D;D;D
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.8	.;L;L
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-7.3	D;D;D
REVEL	Benign	0.25
Sift	Uncertain	0.024	D;D;D
Sift4G	Uncertain	0.045	D;D;D
Polyphen		0.82	P;P;P
Vest4		0.70
MutPred		0.67		.;Gain of relative solvent accessibility (P = 0.1259);Gain of relative solvent accessibility (P = 0.1259);
MVP		0.60
MPC		1.8
ClinPred		0.99	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.43
gMVP		0.97

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: chr10-43696126;