rs869320715

Positions:

• chr17-35557406-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PS1 PM2

The NM_001129820.2(SLFN14):​c.657A>T​(p.Lys219Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,372 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: SLFN14 NM_001129820.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity no assertion criteria provided P:2 U:1
• Conservation: PhyloP100: -0.247

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 6 ACMG points.

• PS1: Transcript NM_001129820.2 (SLFN14) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLFN14	NM_001129820.2	c.657A>T	p.Lys219Asn	missense_variant	3/6	ENST00000674182.1	NP_001123292.1
SLFN14	XM_017024577.2	c.657A>T	p.Lys219Asn	missense_variant	3/6		XP_016880066.1
SLFN14	XM_017024578.2	c.657A>T	p.Lys219Asn	missense_variant	2/5		XP_016880067.1
SLFN14	XM_017024579.2	c.657A>T	p.Lys219Asn	missense_variant	2/5		XP_016880068.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLFN14	ENST00000674182.1	c.657A>T	p.Lys219Asn	missense_variant	3/6		NM_001129820.2	ENSP00000501524	P1
SLFN14	ENST00000415846.3	c.657A>T	p.Lys219Asn	missense_variant	1/4	1		ENSP00000391101	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1399372 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 690188

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Uncertain significance, no assertion criteria provided	research	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 02, 2023	- -

Thrombocytopenia;C1458140:Abnormal bleeding Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	11
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0050	T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.072	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.45	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.069
Sift	Benign	0.16	T
Sift4G	Benign	0.16	T
Polyphen		1.0	D
Vest4		0.73
MutPred		0.37		Loss of methylation at K219 (P = 0.0055);
MVP		0.092
ClinPred		0.31	T
GERP RS		2.6
Varity_R		0.050
gMVP		0.54

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: rs869320715; hg19: chr17-33884425;