17-35548669-T-A

Position:

• chr17-35548669-T-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001129820.2(SLFN14):​c.2309A>T​(p.Tyr770Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0208 in 1,551,768 control chromosomes in the GnomAD database, including 374 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.017 (31 hom., cov: 32)
  • Exomes 𝑓: 0.021 (343 hom.)
• Consequence: SLFN14 NM_001129820.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0560

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0042375326).
• BP6: Variant 17-35548669-T-A is Benign according to our data. Variant chr17-35548669-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 3038068.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0167 (2547/152372) while in subpopulation NFE AF= 0.0238 (1621/68036). AF 95% confidence interval is 0.0229. There are 31 homozygotes in gnomad4. There are 1227 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 31 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLFN14	NM_001129820.2	c.2309A>T	p.Tyr770Phe	missense_variant	6/6	ENST00000674182.1
SLFN14	XM_017024577.2	c.2309A>T	p.Tyr770Phe	missense_variant	6/6
SLFN14	XM_017024578.2	c.2309A>T	p.Tyr770Phe	missense_variant	5/5
SLFN14	XM_017024579.2	c.2309A>T	p.Tyr770Phe	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLFN14	ENST00000674182.1	c.2309A>T	p.Tyr770Phe	missense_variant	6/6		NM_001129820.2	P1
SLFN14	ENST00000415846.3	c.2309A>T	p.Tyr770Phe	missense_variant	4/4	1		P1

Frequencies

GnomAD3 genomes AF: 0.0167 AC: 2549 AN: 152254 Hom.: 31 Cov.: 32

Gnomad AFR AF: 0.00499

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0202

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.0231

Gnomad SAS AF: 0.00683

Gnomad FIN AF: 0.0150

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0239

Gnomad OTH AF: 0.0224

GnomAD3 exomes AF: 0.0166 AC: 2560 AN: 153842 Hom.: 20 AF XY: 0.0160 AC XY: 1308 AN XY: 81608

Gnomad AFR exome AF: 0.00455

Gnomad AMR exome AF: 0.0166

Gnomad ASJ exome AF: 0.00836

Gnomad EAS exome AF: 0.0194

Gnomad SAS exome AF: 0.00703

Gnomad FIN exome AF: 0.0139

Gnomad NFE exome AF: 0.0232

Gnomad OTH exome AF: 0.0183

GnomAD4 exome AF: 0.0212 AC: 29655 AN: 1399396 Hom.: 343 Cov.: 33 AF XY: 0.0207 AC XY: 14273 AN XY: 690208

Gnomad4 AFR exome AF: 0.00440

Gnomad4 AMR exome AF: 0.0168

Gnomad4 ASJ exome AF: 0.0107

Gnomad4 EAS exome AF: 0.0182

Gnomad4 SAS exome AF: 0.00670

Gnomad4 FIN exome AF: 0.0141

Gnomad4 NFE exome AF: 0.0237

Gnomad4 OTH exome AF: 0.0195

GnomAD4 genome AF: 0.0167 AC: 2547 AN: 152372 Hom.: 31 Cov.: 32 AF XY: 0.0165 AC XY: 1227 AN XY: 74506

Gnomad4 AFR AF: 0.00502

Gnomad4 AMR AF: 0.0201

Gnomad4 ASJ AF: 0.0107

Gnomad4 EAS AF: 0.0231

Gnomad4 SAS AF: 0.00642

Gnomad4 FIN AF: 0.0150

Gnomad4 NFE AF: 0.0238

Gnomad4 OTH AF: 0.0227

Alfa AF: 0.0215 Hom.: 35

Bravo AF: 0.0169

TwinsUK AF: 0.0270 AC: 100

ALSPAC AF: 0.0179 AC: 69

ESP6500AA AF: 0.00506 AC: 7

ESP6500EA AF: 0.0239 AC: 76

ExAC AF: 0.0121 AC: 277

Asia WGS AF: 0.0230 AC: 80 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

SLFN14-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 11, 2023

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.0035	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.91	N
REVEL	Benign	0.051
Sift	Benign	0.065	T
Sift4G	Benign	0.10	T
Polyphen		0.94	P
Vest4		0.16
ClinPred		0.014	T
GERP RS		2.9
Varity_R		0.12
gMVP		0.40

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: rs78364481; hg19: chr17-33875688;