Genetic Variant SLFN5:p.Arg180Trp (chr17-35259228-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_144975.4(SLFN5):c.538C>T(p.Arg180Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00007 in 1,613,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000070 ( 0 hom. )

Consequence

SLFN5
NM_144975.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -3.36

Variant links:

Genes affected

SLFN5 (HGNC:28286): (schlafen family member 5) Predicted to enable ATP binding activity. Predicted to be involved in cell differentiation. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

SLFN5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.052084684).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLFN5	NM_144975.4 link	c.538C>T	p.Arg180Trp	missense_variant	Exon 2 of 5	ENST00000299977.9	NP_659412.3	Q08AF3-1
SLFN5	NM_001330183.2 link	c.538C>T	p.Arg180Trp	missense_variant	Exon 2 of 4		NP_001317112.1	B4E128

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLFN5	ENST00000299977.9 link	c.538C>T	p.Arg180Trp	missense_variant	Exon 2 of 5	1	NM_144975.4	ENSP00000299977.3	Q08AF3-1
SLFN5	ENST00000592325.1 link	c.538C>T	p.Arg180Trp	missense_variant	Exon 2 of 2	1		ENSP00000466984.1	Q08AF3-2
SLFN5	ENST00000542451.1 link	c.538C>T	p.Arg180Trp	missense_variant	Exon 2 of 4	2		ENSP00000440537.1	B4E128

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000639

AC:

AN:

250270

Hom.:

AF XY:

0.0000517

AC XY:

AN XY:

135376

show subpopulations

Gnomad AFR exome

AF:

0.0000619

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000698

AC:

102

AN:

1461792

Hom.:

Cov.:

AF XY:

0.0000660

AC XY:

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000150

Gnomad4 NFE exome

AF:

0.0000782

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000107

Hom.:

Bravo

AF:

0.0000718

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000576

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

Dec 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.538C>T (p.R180W) alteration is located in exon 2 (coding exon 1) of the SLFN5 gene. This alteration results from a C to T substitution at nucleotide position 538, causing the arginine (R) at amino acid position 180 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

0.092

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0065

T;.;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.055

LIST_S2

Benign

0.74

T;T;T

M_CAP

Benign

0.0091

MetaRNN

Benign

0.052

T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.2

L;.;L

PrimateAI

Benign

0.21

PROVEAN

Uncertain

-3.1

D;D;.

REVEL

Benign

0.0080

Sift

Benign

0.065

T;T;.

Sift4G

Benign

0.10

T;T;T

Polyphen

0.0030

B;B;B

Vest4

0.27

MVP

0.27

MPC

0.24

ClinPred

0.11

GERP RS

1.4

Varity_R

0.097

gMVP

0.25

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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