15-78962172-A-T

Variant names:

• chr15-78962172-A-T
• NM_001145648.3:c.3746T>A

Variant summary

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

The NM_001145648.3(RASGRF1):​c.3746T>A​(p.Leu1249His) 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RASGRF1 NM_001145648.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.98

Genes affected

RASGRF1 (HGNC:9875): (Ras protein specific guanine nucleotide releasing factor 1) The protein encoded by this gene is a guanine nucleotide exchange factor (GEF) similar to the Saccharomyces cerevisiae CDC25 gene product. Functional analysis has demonstrated that this protein stimulates the dissociation of GDP from RAS protein. The studies of the similar gene in mouse suggested that the Ras-GEF activity of this protein in brain can be activated by Ca2+ influx, muscarinic receptors, and G protein beta-gamma subunit. Mouse studies also indicated that the Ras-GEF signaling pathway mediated by this protein may be important for long-term memory. Alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Mar 2009]

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, 0.807

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RASGRF1	NM_001145648.3	c.3746T>A	p.Leu1249His	missense_variant	Exon 27 of 27	ENST00000558480.7	NP_001139120.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RASGRF1	ENST00000558480.7	c.3746T>A	p.Leu1249His	missense_variant	Exon 27 of 27	2	NM_001145648.3	ENSP00000452781.2
RASGRF1	ENST00000394745.3	c.1442T>A	p.Leu481His	missense_variant	Exon 14 of 14	1		ENSP00000378228.3
RASGRF1	ENST00000419573.7	c.3794T>A	p.Leu1265His	missense_variant	Exon 28 of 28	2		ENSP00000405963.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 29, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3794T>A (p.L1265H) alteration is located in exon 28 (coding exon 28) of the RASGRF1 gene. This alteration results from a T to A substitution at nucleotide position 3794, causing the leucine (L) at amino acid position 1265 to be replaced by a histidine (H). 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	0.99
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.69	.;D;.
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.81	D;D;D
MetaSVM	Benign	-0.55	T
MutationAssessor	Pathogenic	3.3	.;M;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-5.6	.;D;D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0030	.;D;D
Sift4G	Pathogenic	0.0	D;D;D
Vest4		0.66
MVP		0.44
MPC		1.8
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.73
gMVP		0.73

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: chr15-79254514;