chr5-180128436-C-A

Variant names:

• chr5-180128436-C-A
• NM_175062.4:c.613G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_175062.4(RASGEF1C):​c.613G>T​(p.Ala205Ser) variant causes a missense change involving the alteration of a conserved nucleotide. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A205V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RASGEF1C NM_175062.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.25

Genes affected

RASGEF1C (HGNC:27400): (RasGEF domain family member 1C) Predicted to enable guanyl-nucleotide exchange factor activity. Predicted to be involved in regulation of catalytic activity and small GTPase mediated signal transduction. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RASGEF1C	NM_175062.4	c.613G>T	p.Ala205Ser	missense_variant	Exon 5 of 14	ENST00000361132.9	NP_778232.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RASGEF1C	ENST00000361132.9	c.613G>T	p.Ala205Ser	missense_variant	Exon 5 of 14	1	NM_175062.4	ENSP00000354963.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 28, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.613G>T (p.A205S) alteration is located in exon 5 (coding exon 4) of the RASGEF1C gene. This alteration results from a G to T substitution at nucleotide position 613, causing the alanine (A) at amino acid position 205 to be replaced by a serine (S). 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	0.36
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T;.;T;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	.;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Pathogenic	3.3	M;.;M;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.6	D;.;D;D
REVEL	Pathogenic	0.74
Sift	Benign	0.051	T;.;T;D
Sift4G	Uncertain	0.026	D;T;D;T
Polyphen		0.99	D;.;D;.
Vest4		0.81
MutPred		0.86		Gain of disorder (P = 0.073);.;Gain of disorder (P = 0.073);.;
MVP		0.89
MPC		1.2
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.41
gMVP		0.63

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: chr5-179555436;