Genetic Variant RASSF1:p.Arg240His (chr3-50331600-C-T) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_007182.5(RASSF1):c.719G>A(p.Arg240His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000193 in 1,602,498 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R240S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

RASSF1
NM_007182.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.54

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3005071).

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.719G>A	p.Arg240His	missense	Exon 4 of 6	NP_009113.3
RASSF1	NM_170714.2		c.731G>A	p.Arg244His	missense	Exon 4 of 6	NP_733832.1	Q9NS23-1
RASSF1	NM_170713.3		c.509G>A	p.Arg170His	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.719G>A	p.Arg240His	missense	Exon 4 of 6	ENSP00000352323.4	Q9NS23-2
RASSF1	ENST00000357043.6	TSL:1	c.731G>A	p.Arg244His	missense	Exon 4 of 6	ENSP00000349547.2	Q9NS23-1
RASSF1	ENST00000327761.7	TSL:1	c.509G>A	p.Arg170His	missense	Exon 3 of 5	ENSP00000333327.3	Q9NS23-4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000160

AC:

AN:

250180

AF XY:

0.00000739

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000207

AC:

AN:

1450276

Hom.:

Cov.:

AF XY:

0.0000209

AC XY:

AN XY:

718812

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33232

American (AMR)

AF:

0.00

AC:

AN:

44380

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25968

East Asian (EAS)

AF:

0.000254

AC:

AN:

39302

South Asian (SAS)

AF:

0.00

AC:

AN:

86026

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53120

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.0000181

AC:

AN:

1102710

Other (OTH)

AF:

0.00

AC:

AN:

59796

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

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

AF:

0.00000657

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41470

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.41

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.16

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.020

MetaRNN

Benign

0.30

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

PhyloP100

2.5

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.069

Sift

Benign

0.12

Sift4G

Uncertain

0.042

Polyphen

1.0

Vest4

0.30

MVP

0.44

MPC

0.64

ClinPred

0.87

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.12

gMVP

0.47

Mutation Taster

=74/26

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over