rs869320716

chr17-35557411-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

The NM_001129820.2(SLFN14):c.652A>G(p.Lys218Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLFN14 NM_001129820.2 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 U:1
• Conservation: PhyloP100: 1.90

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-35557411-T-C is Pathogenic according to our data. Variant chr17-35557411-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 225535.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.23653913).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLFN14	NM_001129820.2	c.652A>G	p.Lys218Glu	missense_variant	3/6	ENST00000674182.1
SLFN14	XM_017024577.2	c.652A>G	p.Lys218Glu	missense_variant	3/6
SLFN14	XM_017024578.2	c.652A>G	p.Lys218Glu	missense_variant	2/5
SLFN14	XM_017024579.2	c.652A>G	p.Lys218Glu	missense_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLFN14	ENST00000674182.1	c.652A>G	p.Lys218Glu	missense_variant	3/6		NM_001129820.2	P1
SLFN14	ENST00000415846.3	c.652A>G	p.Lys218Glu	missense_variant	1/4	1		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Platelet-type bleeding disorder 20 Pathogenic:2 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 05, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 02, 2023	- -
Uncertain significance, no assertion criteria provided	research	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.0035	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	0.99	N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.12
Sift	Benign	0.57	T
Sift4G	Benign	0.33	T
Polyphen		1.0	D
Vest4		0.35
MutPred		0.37		Loss of MoRF binding (P = 0.0019);
MVP		0.030
ClinPred		0.59	D
GERP RS		4.6
Varity_R		0.14
gMVP		0.46

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: rs869320716; hg19: chr17-33884430;