12-64691569-A-T

Variant names:

• chr12-64691569-A-T
• NM_178169.4:c.557A>T

Variant summary

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

The NM_178169.4(RASSF3):​c.557A>T​(p.Glu186Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000069 in 1,448,806 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. E186A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RASSF3 NM_178169.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.51

Genes affected

RASSF3 (HGNC:14271): (Ras association domain family member 3) The RAS oncogene (MIM 190020) is mutated in nearly one-third of all human cancers. Members of the RAS superfamily are plasma membrane GTP-binding proteins that modulate intracellular signal transduction pathways. A subfamily of RAS effectors, including RASSF3, share a RAS association (RA) domain.[supplied by OMIM, Jul 2003]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RASSF3	NM_178169.4	c.557A>T	p.Glu186Val	missense_variant	Exon 4 of 5	ENST00000542104.6	NP_835463.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RASSF3	ENST00000542104.6	c.557A>T	p.Glu186Val	missense_variant	Exon 4 of 5	1	NM_178169.4	ENSP00000443021.1
RASSF3	ENST00000637125.1	c.740A>T	p.Glu247Val	missense_variant	Exon 5 of 6	5		ENSP00000490100.1
RASSF3	ENST00000283172.8	n.*46A>T		non_coding_transcript_exon_variant	Exon 3 of 4	2		ENSP00000283172.4
RASSF3	ENST00000283172.8	n.*46A>T		3_prime_UTR_variant	Exon 3 of 4	2		ENSP00000283172.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1448806 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 721362

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.08e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.557A>T (p.E186V) alteration is located in exon 4 (coding exon 4) of the RASSF3 gene. This alteration results from a A to T substitution at nucleotide position 557, causing the glutamic acid (E) at amino acid position 186 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	0.42
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	.;T;T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	D;D;.
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.73	D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.0	.;M;M
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-6.2	.;D;D
REVEL	Benign	0.28
Sift	Uncertain	0.0010	.;D;D
Sift4G	Uncertain	0.0030	.;D;D
Polyphen		0.97	.;D;D
Vest4		0.74
MutPred		0.64		.;Loss of disorder (P = 0.1068);Loss of disorder (P = 0.1068);
MVP		0.51
MPC		0.41
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.91
gMVP		0.42

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: chr12-65085349;