17-35548454-G-T

Variant names:

• chr17-35548454-G-T
• rs2072552264
• NM_001129820.2:c.2524C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001129820.2(SLFN14):​c.2524C>A​(p.His842Asn) 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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLFN14 NM_001129820.2 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.576

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 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=0.077640325).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLFN14	NM_001129820.2	c.2524C>A	p.His842Asn	missense_variant	Exon 6 of 6	ENST00000674182.1	NP_001123292.1
SLFN14	XM_017024577.2	c.2524C>A	p.His842Asn	missense_variant	Exon 6 of 6		XP_016880066.1
SLFN14	XM_017024578.2	c.2524C>A	p.His842Asn	missense_variant	Exon 5 of 5		XP_016880067.1
SLFN14	XM_017024579.2	c.2524C>A	p.His842Asn	missense_variant	Exon 5 of 5		XP_016880068.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLFN14	ENST00000674182.1	c.2524C>A	p.His842Asn	missense_variant	Exon 6 of 6		NM_001129820.2	ENSP00000501524.1
SLFN14	ENST00000415846.3	c.2524C>A	p.His842Asn	missense_variant	Exon 4 of 4	1		ENSP00000391101.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

SLFN14-related disorder Uncertain:1

Jun 04, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SLFN14 c.2524C>A variant is predicted to result in the amino acid substitution p.His842Asn. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	1.5
DANN	Benign	0.33
DEOGEN2	Benign	0.0020	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.078	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.1	M
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.051
Sift	Benign	0.63	T
Sift4G	Benign	0.43	T
Polyphen		0.65	P
Vest4		0.15
MutPred		0.23		Gain of sheet (P = 0.0266);
MVP		0.014
ClinPred		0.14	T
GERP RS		2.1
Varity_R		0.065
gMVP		0.27

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: rs2072552264; hg19: chr17-33875473; COSMIC: COSV70570477; COSMIC: COSV70570477;