Genetic Variant RASSF1:p.Arg223Leu (chr3-50331651-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_007182.5(RASSF1):c.668G>T(p.Arg223Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. 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. R223H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

RASSF1
NM_007182.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.66

Publications

2 publications found

Variant links:

Genes affected

RASSF1 (HGNC:9882): (Ras association domain family member 1) This gene encodes a protein similar to the RAS effector proteins. Loss or altered expression of this gene has been associated with the pathogenesis of a variety of cancers, which suggests the tumor suppressor function of this gene. The inactivation of this gene was found to be correlated with the hypermethylation of its CpG-island promoter region. The encoded protein was found to interact with DNA repair protein XPA. The protein was also shown to inhibit the accumulation of cyclin D1, and thus induce cell cycle arrest. Several alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported. [provided by RefSeq, May 2011]

RASSF1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.27421916).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007182.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RASSF1	NM_007182.5	MANE Select	c.668G>T	p.Arg223Leu	missense	Exon 4 of 6	NP_009113.3
RASSF1	NM_170714.2		c.680G>T	p.Arg227Leu	missense	Exon 4 of 6	NP_733832.1	Q9NS23-1
RASSF1	NM_170713.3		c.458G>T	p.Arg153Leu	missense	Exon 3 of 5	NP_733831.1	Q9NS23-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RASSF1	ENST00000359365.9	TSL:1 MANE Select	c.668G>T	p.Arg223Leu	missense	Exon 4 of 6	ENSP00000352323.4	Q9NS23-2
RASSF1	ENST00000357043.6	TSL:1	c.680G>T	p.Arg227Leu	missense	Exon 4 of 6	ENSP00000349547.2	Q9NS23-1
RASSF1	ENST00000327761.7	TSL:1	c.458G>T	p.Arg153Leu	missense	Exon 3 of 5	ENSP00000333327.3	Q9NS23-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

251290

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.00000137

AC:

AN:

1459898

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725770

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33460

American (AMR)

AF:

0.00

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39630

South Asian (SAS)

AF:

0.00

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53276

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110384

Other (OTH)

AF:

0.00

AC:

AN:

60320

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000287

Hom.:

Bravo

AF:

0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.083

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.85

M_CAP

Benign

0.046

MetaRNN

Benign

0.27

MetaSVM

Benign

-0.96

MutationAssessor

Uncertain

2.5

PhyloP100

2.7

PrimateAI

Benign

0.37

PROVEAN

Pathogenic

-4.6

REVEL

Benign

0.15

Sift

Benign

0.16

Sift4G

Uncertain

0.038

Polyphen

0.80

Vest4

0.58

MVP

0.49

MPC

1.1

ClinPred

0.97

GERP RS

4.6

Varity_R

0.36

gMVP

0.54

Mutation Taster

=80/20

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over