17-35548559-G-T

Position:

chr17-35548559-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001129820.2(SLFN14):c.2419C>A(p.Gln807Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000387 in 1,551,714 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SLFN14
NM_001129820.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.726

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07056618).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SLFN14	NM_001129820.2 linkuse as main transcript	c.2419C>A	p.Gln807Lys	missense_variant	6/6	ENST00000674182.1
SLFN14	XM_017024577.2 linkuse as main transcript	c.2419C>A	p.Gln807Lys	missense_variant	6/6
SLFN14	XM_017024578.2 linkuse as main transcript	c.2419C>A	p.Gln807Lys	missense_variant	5/5
SLFN14	XM_017024579.2 linkuse as main transcript	c.2419C>A	p.Gln807Lys	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLFN14	ENST00000674182.1 linkuse as main transcript	c.2419C>A	p.Gln807Lys	missense_variant	6/6		NM_001129820.2	P1	P0C7P3-1
SLFN14	ENST00000415846.3 linkuse as main transcript	c.2419C>A	p.Gln807Lys	missense_variant	4/4	1		P1	P0C7P3-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000130

AC:

AN:

153742

Hom.:

AF XY:

0.0000123

AC XY:

AN XY:

81548

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000168

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000143

AC:

AN:

1399396

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

690208

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000280

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000172

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152318

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ExAC

AF:

0.0000432

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 14, 2020

DNA sequence analysis of the SLFN14 gene demonstrated a sequence change, c.2419C>A, in exon 4 that results in an amino acid change, p.Gln807Lys. This sequence change does not appear to have been previously described in patients with SLFN14-related disorders and has been described in the gnomAD database in two individuals (dbSNP rs564352461). The p.Gln807Lys change affects a highly conserved amino acid residue located in a domain of the SLFN14 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Gln807Lys substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Gln807Lys change remains unknown at this time. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 05, 2022

The c.2419C>A (p.Q807K) alteration is located in exon 4 (coding exon 4) of the SLFN14 gene. This alteration results from a C to A substitution at nucleotide position 2419, causing the glutamine (Q) at amino acid position 807 to be replaced by a lysine (K). 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

0.11

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Benign

0.74

DEOGEN2

Benign

0.0020

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.24

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.72

M_CAP

Benign

0.0074

MetaRNN

Benign

0.071

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.6

MutationTaster

Benign

1.0

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.65

REVEL

Benign

0.065

Sift

Benign

0.32

Sift4G

Benign

0.31

Polyphen

0.80

Vest4

0.26

MutPred

0.34

Gain of methylation at Q807 (P = 3e-04);

MVP

0.055

ClinPred

0.13

GERP RS

4.4

Varity_R

0.15

gMVP

0.51

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