17-35422134-A-C

Variant summary

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

The NM_018042.5(SLFN12):ā€‹c.895T>Gā€‹(p.Cys299Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,613,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 33)
Exomes š‘“: 0.000014 ( 0 hom. )

Consequence

SLFN12
NM_018042.5 missense

Scores

1
1
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.112
Variant links:
Genes affected
SLFN12 (HGNC:25500): (schlafen family member 12) Predicted to act upstream of or within negative regulation of cell population proliferation. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

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=0.15744811).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SLFN12NM_018042.5 linkc.895T>G p.Cys299Gly missense_variant 2/4 ENST00000304905.10 NP_060512.3 Q8IYM2
SLFN12NM_001289009.2 linkc.895T>G p.Cys299Gly missense_variant 2/4 NP_001275938.1 Q8IYM2
SLFN12XM_005257995.6 linkc.895T>G p.Cys299Gly missense_variant 3/5 XP_005258052.1 Q8IYM2
SLFN12XM_024450822.2 linkc.895T>G p.Cys299Gly missense_variant 4/6 XP_024306590.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SLFN12ENST00000304905.10 linkc.895T>G p.Cys299Gly missense_variant 2/41 NM_018042.5 ENSP00000302077.5 Q8IYM2
SLFN12ENST00000394562.5 linkc.895T>G p.Cys299Gly missense_variant 4/61 ENSP00000378063.1 Q8IYM2
SLFN12ENST00000452764.3 linkc.895T>G p.Cys299Gly missense_variant 2/42 ENSP00000394903.2 Q8IYM2

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152142
Hom.:
0
Cov.:
33
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000239
AC:
6
AN:
251476
Hom.:
0
AF XY:
0.0000441
AC XY:
6
AN XY:
135912
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000163
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000137
AC:
20
AN:
1461844
Hom.:
0
Cov.:
35
AF XY:
0.0000193
AC XY:
14
AN XY:
727218
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000128
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152142
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74292
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000480
Hom.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.0000247
AC:
3

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsFeb 06, 2023The c.895T>G (p.C299G) alteration is located in exon 2 (coding exon 1) of the SLFN12 gene. This alteration results from a T to G substitution at nucleotide position 895, causing the cysteine (C) at amino acid position 299 to be replaced by a glycine (G). 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
0.19
BayesDel_addAF
Benign
-0.31
T
BayesDel_noAF
Benign
-0.42
CADD
Benign
7.0
DANN
Benign
0.82
DEOGEN2
Benign
0.094
T;T;T
Eigen
Benign
-0.85
Eigen_PC
Benign
-0.99
FATHMM_MKL
Benign
0.018
N
LIST_S2
Benign
0.45
.;.;T
M_CAP
Benign
0.025
D
MetaRNN
Benign
0.16
T;T;T
MetaSVM
Benign
-0.97
T
MutationAssessor
Uncertain
2.3
M;M;M
PrimateAI
Benign
0.39
T
PROVEAN
Pathogenic
-4.8
D;D;D
REVEL
Benign
0.19
Sift
Benign
0.67
T;T;T
Sift4G
Benign
0.45
T;T;T
Polyphen
0.45
B;B;B
Vest4
0.22
MutPred
0.56
Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);
MVP
0.20
MPC
0.37
ClinPred
0.24
T
GERP RS
-2.4
Varity_R
0.13
gMVP
0.52

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.

Other links and lift over

dbSNP: rs752827821; hg19: chr17-33749153; API