chr20-4786303-A-T

Position:

• chr20-4786303-A-T

Variant summary

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

The NM_014737.3(RASSF2):​c.839T>A​(p.Met280Lys) 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: RASSF2 NM_014737.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.92

Genes affected

RASSF2 (HGNC:9883): (Ras association domain family member 2) This gene encodes a protein that contains a Ras association domain. Similar to its cattle and sheep counterparts, this gene is located near the prion gene. Two alternatively spliced transcripts encoding the same isoform have been reported. [provided by RefSeq, Jul 2008]

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, 0.827

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RASSF2	NM_014737.3	c.839T>A	p.Met280Lys	missense_variant	11/12	ENST00000379400.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RASSF2	ENST00000379400.8	c.839T>A	p.Met280Lys	missense_variant	11/12	1	NM_014737.3	P1
RASSF2	ENST00000379376.2	c.839T>A	p.Met280Lys	missense_variant	10/11	1		P1
RASSF2	ENST00000478553.1	n.809T>A		non_coding_transcript_exon_variant	8/9	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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

Sep 16, 2021

The c.839T>A (p.M280K) alteration is located in exon 11 (coding exon 9) of the RASSF2 gene. This alteration results from a T to A substitution at nucleotide position 839, causing the methionine (M) at amino acid position 280 to be replaced by a lysine (K). 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	0.89
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T;T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.033	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.7	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-4.3	D;D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0080	D;D
Polyphen		1.0	D;D
Vest4		0.89
MutPred		0.58		Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);
MVP		0.72
MPC		1.5
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.86
gMVP		0.86

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

LitVar

Other links and lift over

dbSNP: rs1388502322; hg19: chr20-4766949;