Genetic Variant RASSF3:p.Thr175Ile (chr12-64691536-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_178169.4(RASSF3):c.524C>T(p.Thr175Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000235 in 1,613,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

RASSF3
NM_178169.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.62

Variant links:

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]

RASSF3 links:

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ACMG classification

Classification made for transcript

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=0.15128821).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RASSF3	NM_178169.4 link	c.524C>T	p.Thr175Ile	missense_variant	Exon 4 of 5	ENST00000542104.6	NP_835463.1	Q86WH2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RASSF3	ENST00000542104.6 link	c.524C>T	p.Thr175Ile	missense_variant	Exon 4 of 5	1	NM_178169.4	ENSP00000443021.1	Q86WH2-1
RASSF3	ENST00000637125.1 link	c.707C>T	p.Thr236Ile	missense_variant	Exon 5 of 6	5		ENSP00000490100.1	A0A1B0GUG6
RASSF3	ENST00000283172.8 link	n.*13C>T		non_coding_transcript_exon_variant	Exon 3 of 4	2		ENSP00000283172.4	Q86WH2-2
RASSF3	ENST00000283172.8 link	n.*13C>T		3_prime_UTR_variant	Exon 3 of 4	2		ENSP00000283172.4	Q86WH2-2

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251458

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1461648

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727154

show subpopulations

Gnomad4 AFR exome

AF:

0.000448

Gnomad4 AMR exome

AF:

0.0000671

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.000125

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.524C>T (p.T175I) alteration is located in exon 4 (coding exon 4) of the RASSF3 gene. This alteration results from a C to T substitution at nucleotide position 524, causing the threonine (T) at amino acid position 175 to be replaced by an isoleucine (I). 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

0.31

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.36

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.069

.;T;T

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Benign

0.73

LIST_S2

Uncertain

0.90

D;D;.

M_CAP

Benign

0.015

MetaRNN

Benign

0.15

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.6

.;M;M

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-3.4

.;D;D

REVEL

Benign

0.083

Sift

Benign

0.081

.;T;T

Sift4G

Benign

0.13

.;T;T

Polyphen

0.72

.;P;P

Vest4

0.64

MVP

0.48

MPC

0.35

ClinPred

0.28

GERP RS

4.8

Varity_R

0.19

gMVP

0.34

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over