Genetic Variant RASSF6:p.Ser110Ile (chr4-73587893-C-A) – 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_177532.5(RASSF6):c.329G>T(p.Ser110Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,458,388 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. S110T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

RASSF6
NM_177532.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.88

Publications

0 publications found

Variant links:

Genes affected

RASSF6 (HGNC:20796): (Ras association domain family member 6) This gene encodes a member of the Ras-association domain family (RASSF). Members of this family form the core of a highly conserved tumor suppressor network, the Salvador-Warts-Hippo (SWH) pathway. The protein encoded by this gene is a Ras effector protein that induces apoptosis. A genomic region containing this gene has been linked to susceptibility to viral bronchiolitis. Alternative splicing results in multiple transcript variants and protein isoforms. [provided by RefSeq, Jul 2012]

RASSF6 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;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_177532.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RASSF6	NM_177532.5	MANE Select	c.329G>T	p.Ser110Ile	missense	Exon 5 of 11	NP_803876.1	Q6ZTQ3-2
RASSF6	NM_201431.2		c.425G>T	p.Ser142Ile	missense	Exon 5 of 11	NP_958834.1	Q6ZTQ3-1
RASSF6	NM_001270392.1		c.293G>T	p.Ser98Ile	missense	Exon 4 of 10	NP_001257321.1	Q6ZTQ3-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RASSF6	ENST00000307439.10	TSL:1 MANE Select	c.329G>T	p.Ser110Ile	missense	Exon 5 of 11	ENSP00000303877.5	Q6ZTQ3-2
RASSF6	ENST00000335049.5	TSL:1	c.293G>T	p.Ser98Ile	missense	Exon 4 of 10	ENSP00000335582.5	Q6ZTQ3-3
RASSF6	ENST00000395777.6	TSL:1	c.329G>T	p.Ser110Ile	missense	Exon 5 of 10	ENSP00000379123.2	Q6ZTQ3-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000343

AC:

AN:

1458388

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

725574

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33388

American (AMR)

AF:

0.00

AC:

AN:

44664

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26016

East Asian (EAS)

AF:

0.00

AC:

AN:

39556

South Asian (SAS)

AF:

0.00

AC:

AN:

85994

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53312

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.00000451

AC:

AN:

1109532

Other (OTH)

AF:

0.00

AC:

AN:

60180

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000455559), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.395

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.39

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.035

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.75

M_CAP

Benign

0.026

MetaRNN

Uncertain

0.60

MetaSVM

Benign

-0.93

MutationAssessor

Uncertain

2.6

PhyloP100

1.9

PrimateAI

Benign

0.37

PROVEAN

Uncertain

-3.5

REVEL

Benign

0.12

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.030

Polyphen

0.95

Vest4

0.63

MutPred

0.43

Gain of glycosylation at Y139 (P = 7e-04)

MVP

0.31

MPC

0.010

ClinPred

0.99

GERP RS

4.8

Varity_R

0.45

gMVP

0.51

Mutation Taster

=87/13

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