Genetic Variant SLFNL1:p.Arg280Cys (chr1-41017754-G-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_144990.4(SLFNL1):c.838C>T(p.Arg280Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000174 in 1,607,866 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 (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

SLFNL1
NM_144990.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.84

Variant links:

Genes affected

SLFNL1 (HGNC:26313): (schlafen like 1) Predicted to enable ATP binding activity. [provided by Alliance of Genome Resources, Apr 2022]

SLFNL1 links:

SLFNL1-AS1 (HGNC:44126): (SLFNL1 antisense RNA 1)

SLFNL1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.841

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLFNL1	NM_144990.4 link	c.838C>T	p.Arg280Cys	missense_variant	Exon 4 of 6	ENST00000302946.13	NP_659427.3	Q499Z3-1A0A140VJU6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLFNL1	ENST00000302946.13 link	c.838C>T	p.Arg280Cys	missense_variant	Exon 4 of 6	1	NM_144990.4	ENSP00000304401.8		Q499Z3-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152204

Hom.:

Cov.:

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:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000243

AC:

AN:

247306

Hom.:

AF XY:

0.0000224

AC XY:

AN XY:

133758

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:

0.0000667

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000269

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.0000179

AC:

AN:

1455544

Hom.:

Cov.:

AF XY:

0.0000207

AC XY:

AN XY:

723152

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:

0.0000584

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.0000333

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152322

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74476

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:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.00000756

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 30, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.838C>T (p.R280C) alteration is located in exon 4 (coding exon 2) of the SLFNL1 gene. This alteration results from a C to T substitution at nucleotide position 838, causing the arginine (R) at amino acid position 280 to be replaced by a cysteine (C). 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

0.26

BayesDel_addAF

Uncertain

0.075

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.088

T;.;T;.;T

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Benign

0.75

LIST_S2

Uncertain

0.91

.;D;D;D;.

M_CAP

Benign

0.044

MetaRNN

Pathogenic

0.84

D;D;D;D;D

MetaSVM

Benign

-0.72

MutationAssessor

Pathogenic

3.1

M;M;M;.;M

PrimateAI

Benign

0.47

PROVEAN

Pathogenic

-4.6

D;D;D;D;D

REVEL

Uncertain

0.41

Sift

Uncertain

0.0030

D;D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D

Polyphen

1.0

D;D;D;D;D

Vest4

0.78

MutPred

0.59

Loss of disorder (P = 0.006);Loss of disorder (P = 0.006);Loss of disorder (P = 0.006);.;Loss of disorder (P = 0.006);

MVP

0.24

MPC

0.38

ClinPred

0.97

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.23

gMVP

0.58

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