rs869320716

Variant names:

• chr17-35557411-T-C
• rs869320716
• NM_001129820.2:c.652A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 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. 13/22 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
• Publications: 14 publications found

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 Gene-Disease associations (from GenCC):

• platelet-type bleeding disorder 20

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001129820.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLFN14	NM_001129820.2	MANE Select	c.652A>G	p.Lys218Glu	missense	Exon 3 of 6	NP_001123292.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLFN14	ENST00000674182.1	MANE Select	c.652A>G	p.Lys218Glu	missense	Exon 3 of 6	ENSP00000501524.1
	SLFN14	ENST00000415846.3	TSL:1	c.652A>G	p.Lys218Glu	missense	Exon 1 of 4	ENSP00000391101.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	1	-	Platelet-type bleeding disorder 20 (3)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		1.9
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
Mutation Taster		=28/72	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs869320716; hg19: chr17-33884430;