Genetic Variant SLFN11:p.Arg855Trp (chr17-35352499-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_001376007.1(SLFN11):c.2563C>T(p.Arg855Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000564 in 1,614,110 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 (★).

Frequency

Genomes: 𝑓 0.00029 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

SLFN11
NM_001376007.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.45

Variant links:

Genes affected

SLFN11 (HGNC:26633): (schlafen family member 11) Enables tRNA binding activity. Involved in several processes, including defense response to virus; negative regulation of G1/S transition of mitotic cell cycle; and replication fork arrest. Located in cytosol; nucleoplasm; and site of DNA damage. [provided by Alliance of Genome Resources, Apr 2022]

SLFN11 links:

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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=0.11592093).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLFN11	NM_001376007.1 link	c.2563C>T	p.Arg855Trp	missense_variant	Exon 7 of 7	ENST00000685675.1	NP_001362936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLFN11	ENST00000685675.1 link	c.2563C>T	p.Arg855Trp	missense_variant	Exon 7 of 7		NM_001376007.1	ENSP00000510787.1	Q7Z7L1
SLFN11	ENST00000308377.8 link	c.2563C>T	p.Arg855Trp	missense_variant	Exon 5 of 5	1		ENSP00000312402.4	Q7Z7L1
SLFN11	ENST00000394566.5 link	c.2563C>T	p.Arg855Trp	missense_variant	Exon 7 of 7	2		ENSP00000378067.1	Q7Z7L1
SLFN11	ENST00000592108 link	c.*372C>T		3_prime_UTR_variant	Exon 2 of 2	5		ENSP00000465198.1	K7EJJ3

Frequencies

GnomAD3 genomes

AF:

0.000289

AC:

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000942

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000716

AC:

AN:

251492

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.000800

Gnomad AMR exome

AF:

0.0000578

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:

0.0000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000322

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.000717

Gnomad4 AMR exome

AF:

0.000112

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:

0.0000153

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.000289

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.000939

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000389

Hom.:

Bravo

AF:

0.000272

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2563C>T (p.R855W) alteration is located in exon 7 (coding exon 4) of the SLFN11 gene. This alteration results from a C to T substitution at nucleotide position 2563, causing the arginine (R) at amino acid position 855 to be replaced by a tryptophan (W). 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

-0.090

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

T;T

Eigen

Benign

-0.095

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.085

LIST_S2

Benign

0.48

.;T

M_CAP

Benign

0.019

MetaRNN

Benign

0.12

T;T

MetaSVM

Benign

-0.30

MutationAssessor

Uncertain

2.6

M;M

PrimateAI

Benign

0.38

PROVEAN

Pathogenic

-5.2

D;D

REVEL

Uncertain

0.47

Sift

Benign

0.030

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

1.0

D;D

Vest4

0.42

MVP

0.62

MPC

0.051

ClinPred

0.52

GERP RS

1.8

Varity_R

0.15

gMVP

0.26

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over