rs10512472

Positions:

• chr17-35557785-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001129820.2(SLFN14):​c.278A>G​(p.Gln93Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.187 in 1,551,612 control chromosomes in the GnomAD database, including 28,328 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.20 (3002 hom., cov: 32)
  • Exomes 𝑓: 0.19 (25326 hom.)
• Consequence: SLFN14 NM_001129820.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.11

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037332773).
• BP6: Variant 17-35557785-T-C is Benign according to our data. Variant chr17-35557785-T-C is described in ClinVar as [Benign]. Clinvar id is 1333129.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.326 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLFN14	NM_001129820.2	c.278A>G	p.Gln93Arg	missense_variant	3/6	ENST00000674182.1	NP_001123292.1
SLFN14	XM_017024577.2	c.278A>G	p.Gln93Arg	missense_variant	3/6		XP_016880066.1
SLFN14	XM_017024578.2	c.278A>G	p.Gln93Arg	missense_variant	2/5		XP_016880067.1
SLFN14	XM_017024579.2	c.278A>G	p.Gln93Arg	missense_variant	2/5		XP_016880068.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLFN14	ENST00000674182.1	c.278A>G	p.Gln93Arg	missense_variant	3/6		NM_001129820.2	ENSP00000501524	P1
SLFN14	ENST00000415846.3	c.278A>G	p.Gln93Arg	missense_variant	1/4	1		ENSP00000391101	P1

Frequencies

GnomAD3 genomes AF: 0.196 AC: 29840 AN: 152100 Hom.: 2995 Cov.: 32

Gnomad AFR AF: 0.206

Gnomad AMI AF: 0.113

Gnomad AMR AF: 0.219

Gnomad ASJ AF: 0.251

Gnomad EAS AF: 0.339

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.185

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.172

Gnomad OTH AF: 0.213

GnomAD3 exomes AF: 0.209 AC: 32173 AN: 154038 Hom.: 3635 AF XY: 0.208 AC XY: 17009 AN XY: 81734

Gnomad AFR exome AF: 0.213

Gnomad AMR exome AF: 0.235

Gnomad ASJ exome AF: 0.250

Gnomad EAS exome AF: 0.333

Gnomad SAS exome AF: 0.218

Gnomad FIN exome AF: 0.177

Gnomad NFE exome AF: 0.173

Gnomad OTH exome AF: 0.216

GnomAD4 exome AF: 0.186 AC: 260020 AN: 1399392 Hom.: 25326 Cov.: 33 AF XY: 0.187 AC XY: 128939 AN XY: 690206

Gnomad4 AFR exome AF: 0.203

Gnomad4 AMR exome AF: 0.238

Gnomad4 ASJ exome AF: 0.243

Gnomad4 EAS exome AF: 0.358

Gnomad4 SAS exome AF: 0.220

Gnomad4 FIN exome AF: 0.177

Gnomad4 NFE exome AF: 0.173

Gnomad4 OTH exome AF: 0.199

GnomAD4 genome AF: 0.196 AC: 29872 AN: 152220 Hom.: 3002 Cov.: 32 AF XY: 0.199 AC XY: 14826 AN XY: 74420

Gnomad4 AFR AF: 0.206

Gnomad4 AMR AF: 0.219

Gnomad4 ASJ AF: 0.251

Gnomad4 EAS AF: 0.340

Gnomad4 SAS AF: 0.226

Gnomad4 FIN AF: 0.185

Gnomad4 NFE AF: 0.172

Gnomad4 OTH AF: 0.217

Alfa AF: 0.186 Hom.: 6597

Bravo AF: 0.203

TwinsUK AF: 0.164 AC: 608

ALSPAC AF: 0.178 AC: 686

ESP6500AA AF: 0.208 AC: 288

ESP6500EA AF: 0.173 AC: 549

ExAC AF: 0.190 AC: 4205

Asia WGS AF: 0.290 AC: 1011 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

SLFN14-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Platelet-type bleeding disorder 20 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0035	T
Eigen	Benign	0.16
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.058
Sift	Uncertain	0.014	D
Sift4G	Benign	0.24	T
Polyphen		0.80	P
Vest4		0.083
ClinPred		0.027	T
GERP RS		4.3
Varity_R		0.15
gMVP		0.16

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

Other links and lift over

dbSNP: rs10512472; hg19: chr17-33884804; COSMIC: COSV70570297; COSMIC: COSV70570297;