4-73587882-T-C

Position:

• chr4-73587882-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000307439.10(RASSF6):​c.340A>G​(p.Arg114Gly) 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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: RASSF6 ENST00000307439.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.75

Genes affected

RASSF6 (HGNC:20796): (Ras association domain family member 6) This gene encodes a member of the Ras-association domain family (RASSF). Members of this family form the core of a highly conserved tumor suppressor network, the Salvador-Warts-Hippo (SWH) pathway. The protein encoded by this gene is a Ras effector protein that induces apoptosis. A genomic region containing this gene has been linked to susceptibility to viral bronchiolitis. Alternative splicing results in multiple transcript variants and protein isoforms. [provided by RefSeq, Jul 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11091375).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RASSF6	NM_177532.5	c.340A>G	p.Arg114Gly	missense_variant	5/11	ENST00000307439.10	NP_803876.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RASSF6	ENST00000307439.10	c.340A>G	p.Arg114Gly	missense_variant	5/11	1	NM_177532.5	ENSP00000303877	P1
RASSF6	ENST00000335049.5	c.304A>G	p.Arg102Gly	missense_variant	4/10	1		ENSP00000335582
RASSF6	ENST00000395777.6	c.340A>G	p.Arg114Gly	missense_variant	5/10	1		ENSP00000379123
RASSF6	ENST00000342081.7	c.436A>G	p.Arg146Gly	missense_variant	5/11	2		ENSP00000340578

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 31

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

Feb 21, 2024

The c.436A>G (p.R146G) alteration is located in exon 5 (coding exon 5) of the RASSF6 gene. This alteration results from a A to G substitution at nucleotide position 436, causing the arginine (R) at amino acid position 146 to be replaced by a glycine (G). 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	Benign	0.077
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0090	.;T;.;.
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.82	T;T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.11	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	.;M;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-2.7	D;D;D;D
REVEL	Benign	0.048
Sift	Benign	0.22	T;T;T;T
Sift4G	Benign	0.28	T;T;T;T
Polyphen		0.70, 0.69, 0.80	.;P;P;P
Vest4		0.23
MutPred		0.27		.;Gain of glycosylation at S142 (P = 0.0262);.;.;
MVP		0.33
MPC		0.0041
ClinPred		0.67	D
GERP RS		4.5
Varity_R		0.20
gMVP		0.28

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: chr4-74453599;