17-35548286-C-G

Position:

• chr17-35548286-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001129820.2(SLFN14):​c.2692G>C​(p.Ala898Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000715 in 1,399,378 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: SLFN14 NM_001129820.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.41

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.84

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLFN14	NM_001129820.2	c.2692G>C	p.Ala898Pro	missense_variant	6/6	ENST00000674182.1	NP_001123292.1
SLFN14	XM_017024577.2	c.2692G>C	p.Ala898Pro	missense_variant	6/6		XP_016880066.1
SLFN14	XM_017024578.2	c.2692G>C	p.Ala898Pro	missense_variant	5/5		XP_016880067.1
SLFN14	XM_017024579.2	c.2692G>C	p.Ala898Pro	missense_variant	5/5		XP_016880068.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLFN14	ENST00000674182.1	c.2692G>C	p.Ala898Pro	missense_variant	6/6		NM_001129820.2	ENSP00000501524.1
SLFN14	ENST00000415846.3	c.2692G>C	p.Ala898Pro	missense_variant	4/4	1		ENSP00000391101.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1399378 Hom.: 0 Cov.: 33 AF XY: 0.00000145 AC XY: 1 AN XY: 690202

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.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 06, 2017

The A898P variant in the SLFN14 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The A898P variant is not observed in large population cohorts (Lek et al., 2016). The A898P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret A898P as a variant of uncertain significance, which may be related to the reported easy bruising in this individual. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.020	T
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.9	M
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.35
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.78
MutPred		0.66		Loss of helix (P = 0.0237);
MVP		0.48
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.84
gMVP		0.81

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: rs1555547134; hg19: chr17-33875305;