chr17-35548669-T-A

Variant names:

• chr17-35548669-T-A
• rs78364481
• NM_001129820.2:c.2309A>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001129820.2(SLFN14):​c.2309A>T​(p.Tyr770Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0208 in 1,551,768 control chromosomes in the GnomAD database, including 374 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.017 (31 hom., cov: 32)
  • Exomes 𝑓: 0.021 (343 hom.)
• Consequence: SLFN14 NM_001129820.2 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.0560
• Publications: 6 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: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Ambry Genetics, PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0042375326).
• BP6: Variant 17-35548669-T-A is Benign according to our data. Variant chr17-35548669-T-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3038068.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0167 (2547/152372) while in subpopulation NFE AF = 0.0238 (1621/68036). AF 95% confidence interval is 0.0229. There are 31 homozygotes in GnomAd4. There are 1227 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2547 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLFN14	NM_001129820.2	MANE Select	c.2309A>T	p.Tyr770Phe	missense	Exon 6 of 6	NP_001123292.1	P0C7P3-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLFN14	ENST00000674182.1	MANE Select	c.2309A>T	p.Tyr770Phe	missense	Exon 6 of 6	ENSP00000501524.1	P0C7P3-1
	SLFN14	ENST00000415846.3	TSL:1	c.2309A>T	p.Tyr770Phe	missense	Exon 4 of 4	ENSP00000391101.2	P0C7P3-1

Frequencies

GnomAD3 genomes AF: 0.0167 AC: 2549 AN: 152254 Hom.: 31 Cov.: 32

Gnomad AFR AF: 0.00499

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0202

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.0231

Gnomad SAS AF: 0.00683

Gnomad FIN AF: 0.0150

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0239

Gnomad OTH AF: 0.0224

GnomAD2 exomes AF: 0.0166 AC: 2560 AN: 153842 AF XY: 0.0160

Gnomad AFR exome AF: 0.00455

Gnomad AMR exome AF: 0.0166

Gnomad ASJ exome AF: 0.00836

Gnomad EAS exome AF: 0.0194

Gnomad FIN exome AF: 0.0139

Gnomad NFE exome AF: 0.0232

Gnomad OTH exome AF: 0.0183

GnomAD4 exome AF: 0.0212 AC: 29655 AN: 1399396 Hom.: 343 Cov.: 33 AF XY: 0.0207 AC XY: 14273 AN XY: 690208

African (AFR) AF: 0.00440 AC: 139 AN: 31596

American (AMR) AF: 0.0168 AC: 601 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.0107 AC: 270 AN: 25182

East Asian (EAS) AF: 0.0182 AC: 650 AN: 35738

South Asian (SAS) AF: 0.00670 AC: 531 AN: 79236

European-Finnish (FIN) AF: 0.0141 AC: 693 AN: 49276

Middle Eastern (MID) AF: 0.0204 AC: 116 AN: 5698

European-Non Finnish (NFE) AF: 0.0237 AC: 25522 AN: 1078966

Other (OTH) AF: 0.0195 AC: 1133 AN: 58000

GnomAD4 genome AF: 0.0167 AC: 2547 AN: 152372 Hom.: 31 Cov.: 32 AF XY: 0.0165 AC XY: 1227 AN XY: 74506

African (AFR) AF: 0.00502 AC: 209 AN: 41592

American (AMR) AF: 0.0201 AC: 308 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0107 AC: 37 AN: 3470

East Asian (EAS) AF: 0.0231 AC: 120 AN: 5188

South Asian (SAS) AF: 0.00642 AC: 31 AN: 4826

European-Finnish (FIN) AF: 0.0150 AC: 159 AN: 10630

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0238 AC: 1621 AN: 68036

Other (OTH) AF: 0.0227 AC: 48 AN: 2116

Alfa AF: 0.0215 Hom.: 35

Bravo AF: 0.0169

TwinsUK AF: 0.0270 AC: 100

ALSPAC AF: 0.0179 AC: 69

ESP6500AA AF: 0.00506 AC: 7

ESP6500EA AF: 0.0239 AC: 76

ExAC AF: 0.0121 AC: 277

Asia WGS AF: 0.0230 AC: 80 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	SLFN14-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.0035	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.056
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.91	N
REVEL	Benign	0.051
Sift	Benign	0.065	T
Sift4G	Benign	0.10	T
Polyphen		0.94	P
Vest4		0.16
ClinPred		0.014	T
GERP RS		2.9
Varity_R		0.12
gMVP		0.40
Mutation Taster		=100/0	polymorphism

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: rs78364481; hg19: chr17-33875688;