chr13-113981802-A-C

Variant names:

• chr13-113981802-A-C
• NM_007368.4:c.2302T>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_007368.4(RASA3):​c.2302T>G​(p.Phe768Val) 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: 33)
• Consequence: RASA3 NM_007368.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.20
• Publications: 0 publications found

Genes affected

RASA3 (HGNC:20331): (RAS p21 protein activator 3) This gene encodes a protein that binds inositol 1,3,4,5-tetrakisphosphate and stimulates the GTPase activity of Ras p21. This protein functions as a negative regulator of the Ras signalling pathway. It is localized to the cell membrane via a pleckstrin homology (PH) domain in the C-terminal region. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.862

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RASA3	NM_007368.4	c.2302T>G	p.Phe768Val	missense_variant	Exon 23 of 24	ENST00000334062.8	NP_031394.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RASA3	ENST00000334062.8	c.2302T>G	p.Phe768Val	missense_variant	Exon 23 of 24	1	NM_007368.4	ENSP00000335029.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 10, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2302T>G (p.F768V) alteration is located in exon 23 (coding exon 23) of the RASA3 gene. This alteration results from a T to G substitution at nucleotide position 2302, causing the phenylalanine (F) at amino acid position 768 to be replaced by a valine (V). 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	0.47
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Benign	23
DANN	Benign	0.84
DEOGEN2	Uncertain	0.43	T
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		8.2
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.5	D
REVEL	Pathogenic	0.66
Sift	Benign	0.094	T
Sift4G	Benign	0.095	T
Polyphen		0.90	P
Vest4		0.85
MutPred		0.37		Gain of helix (P = 0.0425);
MVP		0.91
MPC		1.4
ClinPred		0.79	D
GERP RS		4.9
Varity_R		0.26
gMVP		0.71
Mutation Taster		=64/36	polymorphism

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

Other links and lift over

hg19: chr13-114751213;