17-35422238-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_018042.5(SLFN12):ā€‹c.791T>Cā€‹(p.Ile264Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,934 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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‘“: 0.0000048 ( 0 hom. )

Consequence

SLFN12
NM_018042.5 missense

Scores

1
5
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.94
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 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.754

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SLFN12NM_018042.5 linkc.791T>C p.Ile264Thr missense_variant 2/4 ENST00000304905.10 NP_060512.3 Q8IYM2
SLFN12NM_001289009.2 linkc.791T>C p.Ile264Thr missense_variant 2/4 NP_001275938.1 Q8IYM2
SLFN12XM_005257995.6 linkc.791T>C p.Ile264Thr missense_variant 3/5 XP_005258052.1 Q8IYM2
SLFN12XM_024450822.2 linkc.791T>C p.Ile264Thr missense_variant 4/6 XP_024306590.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SLFN12ENST00000304905.10 linkc.791T>C p.Ile264Thr missense_variant 2/41 NM_018042.5 ENSP00000302077.5 Q8IYM2
SLFN12ENST00000394562.5 linkc.791T>C p.Ile264Thr missense_variant 4/61 ENSP00000378063.1 Q8IYM2
SLFN12ENST00000452764.3 linkc.791T>C p.Ile264Thr missense_variant 2/42 ENSP00000394903.2 Q8IYM2

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152094
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:
0.0000119
AC:
3
AN:
251302
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135850
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:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000479
AC:
7
AN:
1461840
Hom.:
0
Cov.:
35
AF XY:
0.00000825
AC XY:
6
AN XY:
727212
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
0.00000629
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152094
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74270
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:
0.0000761
Hom.:
0
Bravo
AF:
0.00000756
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.00000824
AC:
1

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 GeneticsMay 04, 2023The c.791T>C (p.I264T) alteration is located in exon 2 (coding exon 1) of the SLFN12 gene. This alteration results from a T to C substitution at nucleotide position 791, causing the isoleucine (I) at amino acid position 264 to be replaced by a threonine (T). 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
0.17
BayesDel_addAF
Benign
-0.0098
T
BayesDel_noAF
Benign
-0.24
CADD
Benign
16
DANN
Benign
0.79
DEOGEN2
Benign
0.22
T;T;T
Eigen
Benign
0.00038
Eigen_PC
Benign
-0.26
FATHMM_MKL
Benign
0.16
N
LIST_S2
Benign
0.48
.;.;T
M_CAP
Benign
0.055
D
MetaRNN
Pathogenic
0.75
D;D;D
MetaSVM
Benign
-0.64
T
MutationAssessor
Uncertain
2.3
M;M;M
PrimateAI
Uncertain
0.59
T
PROVEAN
Uncertain
-4.0
D;D;D
REVEL
Uncertain
0.34
Sift
Benign
0.11
T;T;T
Sift4G
Uncertain
0.045
D;D;D
Polyphen
1.0
D;D;D
Vest4
0.65
MVP
0.73
MPC
0.066
ClinPred
0.55
D
GERP RS
3.3
Varity_R
0.091
gMVP
0.75

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: rs146449318; hg19: chr17-33749257; API