Genetic Variant NM_014737.3:c.839T>C (chr20-4786303-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014737.3(RASSF2):c.839T>C(p.Met280Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,158 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M280K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

RASSF2
NM_014737.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.92

Publications

0 publications found

Variant links:

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]

RASSF2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 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
RASSF2	NM_014737.3 link	c.839T>C	p.Met280Thr	missense_variant	Exon 11 of 12	ENST00000379400.8	NP_055552.1	P50749-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RASSF2	ENST00000379400.8 link	c.839T>C	p.Met280Thr	missense_variant	Exon 11 of 12	1	NM_014737.3	ENSP00000368710.3	P50749-1
RASSF2	ENST00000379376.2 link	c.839T>C	p.Met280Thr	missense_variant	Exon 10 of 11	1		ENSP00000368684.2	P50749-1
RASSF2	ENST00000478553.1 link	n.809T>C		non_coding_transcript_exon_variant	Exon 8 of 9	1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460158

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726584

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33440

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86206

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1110462

Other (OTH)

AF:

0.00

AC:

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.21

T;T

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

.;D

M_CAP

Benign

0.041

MetaRNN

Uncertain

0.74

D;D

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.7

M;M

PhyloP100

8.9

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-3.7

D;D

REVEL

Uncertain

0.50

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.014

D;D

Polyphen

0.98

D;D

Vest4

0.88

MutPred

0.39

Gain of phosphorylation at M280 (P = 0.0452);Gain of phosphorylation at M280 (P = 0.0452);

MVP

0.72

MPC

1.3

ClinPred

0.99

GERP RS

5.3

Varity_R

0.66

gMVP

0.70

Mutation Taster

=58/42

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over