Genetic Variant SLFN14:p.Arg827His (chr17-35548498-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_001129820.2(SLFN14):c.2480G>A(p.Arg827His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000175 in 1,551,730 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000098 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00018 ( 2 hom. )

Consequence

SLFN14
NM_001129820.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.568

Variant links:

Genes affected

SLFN14 (HGNC:32689): (schlafen family member 14) The protein encoded by this gene plays an important role in platelet formation and function. Defects in this gene are a cause of thrombocytopenia with excessive bleeding. [provided by RefSeq, Jul 2016]

SLFN14 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007407367).

BP6

Variant 17-35548498-C-T is Benign according to our data. Variant chr17-35548498-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3892506.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLFN14	NM_001129820.2 link	c.2480G>A	p.Arg827His	missense_variant	Exon 6 of 6	ENST00000674182.1	NP_001123292.1	P0C7P3-1
SLFN14	XM_017024577.2 link	c.2480G>A	p.Arg827His	missense_variant	Exon 6 of 6		XP_016880066.1	P0C7P3-1
SLFN14	XM_017024578.2 link	c.2480G>A	p.Arg827His	missense_variant	Exon 5 of 5		XP_016880067.1	P0C7P3-1
SLFN14	XM_017024579.2 link	c.2480G>A	p.Arg827His	missense_variant	Exon 5 of 5		XP_016880068.1	P0C7P3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLFN14	ENST00000674182.1 link	c.2480G>A	p.Arg827His	missense_variant	Exon 6 of 6		NM_001129820.2	ENSP00000501524.1		P0C7P3-1
SLFN14	ENST00000415846.3 link	c.2480G>A	p.Arg827His	missense_variant	Exon 4 of 4	1		ENSP00000391101.2		P0C7P3-1

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152222

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:

0.00115

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000526

AC:

AN:

153952

Hom.:

AF XY:

0.000686

AC XY:

AN XY:

81688

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000550

Gnomad SAS exome

AF:

0.00329

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000184

AC:

257

AN:

1399390

Hom.:

Cov.:

AF XY:

0.000255

AC XY:

176

AN XY:

690206

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000224

Gnomad4 SAS exome

AF:

0.00290

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000371

Gnomad4 OTH exome

AF:

0.000224

GnomAD4 genome

AF:

0.0000985

AC:

AN:

152340

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00135

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000138

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.00105

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Platelet-type bleeding disorder 20

Benign:1

May 12, 2020

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.68

CADD

Benign

DANN

Benign

0.77

DEOGEN2

Benign

0.00098

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.71

M_CAP

Benign

0.0067

MetaRNN

Benign

0.0074

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.4

PrimateAI

Benign

0.21

PROVEAN

Benign

-1.2

REVEL

Benign

0.015

Sift

Benign

0.38

Sift4G

Benign

0.50

Polyphen

0.0010

Vest4

0.11

MutPred

0.29

Loss of MoRF binding (P = 0.0214);

MVP

0.014

ClinPred

0.025

GERP RS

2.2

Varity_R

0.029

gMVP

0.27

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