19-15452073-C-A

Variant names:

• chr19-15452073-C-A
• NM_022904.3:c.2864G>T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_022904.3(RASAL3):​c.2864G>T​(p.Ser955Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: RASAL3 NM_022904.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.485

Genes affected

RASAL3 (HGNC:26129): (RAS protein activator like 3) This gene belongs to the Ras GTPase-activating proteins (RasGAP) family and encodes a protein with pleckstrin homology (PH), C2, and Ras GTPase-activation protein (RasGAP) domains. This protein is localized near or at the plasma membrane when expressed exogenously. Reduced expression of this gene in some cell lines resulted in increased levels of the active form of Ras (Ras-GTP), suggesting that this gene may play a role in negatively regulating the Ras signaling pathway. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2017]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.065853596).
• BP6: Variant 19-15452073-C-A is Benign according to our data. Variant chr19-15452073-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 3430565.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RASAL3	NM_022904.3	c.2864G>T	p.Ser955Ile	missense_variant	Exon 17 of 18	ENST00000343625.12	NP_075055.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RASAL3	ENST00000343625.12	c.2864G>T	p.Ser955Ile	missense_variant	Exon 17 of 18	2	NM_022904.3	ENSP00000341905.5
RASAL3	ENST00000609274	c.*581G>T		3_prime_UTR_variant	Exon 4 of 4	2		ENSP00000476634.1
RASAL3	ENST00000599694.1	c.1192-135G>T		intron_variant	Intron 6 of 6	5		ENSP00000468841.1
RASAL3	ENST00000602101.6	n.3935G>T		non_coding_transcript_exon_variant	Exon 15 of 16	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Oct 28, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	6.1
DANN	Benign	0.81
DEOGEN2	Benign	0.0086	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.23	T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	2.0	M
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.18
Sift	Benign	0.081	T
Sift4G	Benign	0.19	T
Polyphen		0.0	B
Vest4		0.075
MutPred		0.20		Gain of catalytic residue at S955 (P = 0.0043);
MVP		0.26
MPC		0.0097
ClinPred		0.045	T
GERP RS		0.032
Varity_R		0.069
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: chr19-15562884;