17-35548243-T-A

Variant names:

• chr17-35548243-T-A
• rs8073060
• NM_001129820.2:c.2735A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001129820.2(SLFN14):​c.2735A>T​(p.Tyr912Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.304 in 1,548,762 control chromosomes in the GnomAD database, including 74,475 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (9270 hom., cov: 32)
  • Exomes 𝑓: 0.30 (65205 hom.)
• Consequence: SLFN14 NM_001129820.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.746
• Publications: 28 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021972358).
• BP6: Variant 17-35548243-T-A is Benign according to our data. Variant chr17-35548243-T-A is described in ClinVar as Benign. ClinVar VariationId is 1245977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.45 is higher than 0.05.

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.2735A>T	p.Tyr912Phe	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.2735A>T	p.Tyr912Phe	missense	Exon 6 of 6	ENSP00000501524.1	P0C7P3-1
	SLFN14	ENST00000415846.3	TSL:1	c.2735A>T	p.Tyr912Phe	missense	Exon 4 of 4	ENSP00000391101.2	P0C7P3-1

Frequencies

GnomAD3 genomes AF: 0.338 AC: 51312 AN: 151978 Hom.: 9248 Cov.: 32

Gnomad AFR AF: 0.455

Gnomad AMI AF: 0.173

Gnomad AMR AF: 0.306

Gnomad ASJ AF: 0.408

Gnomad EAS AF: 0.177

Gnomad SAS AF: 0.392

Gnomad FIN AF: 0.242

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.294

Gnomad OTH AF: 0.348

GnomAD2 exomes AF: 0.315 AC: 48301 AN: 153136 AF XY: 0.319

Gnomad AFR exome AF: 0.450

Gnomad AMR exome AF: 0.300

Gnomad ASJ exome AF: 0.411

Gnomad EAS exome AF: 0.179

Gnomad FIN exome AF: 0.240

Gnomad NFE exome AF: 0.307

Gnomad OTH exome AF: 0.331

GnomAD4 exome AF: 0.300 AC: 419536 AN: 1396666 Hom.: 65205 Cov.: 33 AF XY: 0.303 AC XY: 208349 AN XY: 688614

African (AFR) AF: 0.458 AC: 14380 AN: 31390

American (AMR) AF: 0.298 AC: 10560 AN: 35428

Ashkenazi Jewish (ASJ) AF: 0.407 AC: 10225 AN: 25118

East Asian (EAS) AF: 0.156 AC: 5556 AN: 35708

South Asian (SAS) AF: 0.380 AC: 30084 AN: 79172

European-Finnish (FIN) AF: 0.240 AC: 11799 AN: 49148

Middle Eastern (MID) AF: 0.454 AC: 2582 AN: 5684

European-Non Finnish (NFE) AF: 0.294 AC: 316172 AN: 1077180

Other (OTH) AF: 0.314 AC: 18178 AN: 57838

GnomAD4 genome AF: 0.338 AC: 51396 AN: 152096 Hom.: 9270 Cov.: 32 AF XY: 0.334 AC XY: 24834 AN XY: 74342

African (AFR) AF: 0.456 AC: 18895 AN: 41474

American (AMR) AF: 0.307 AC: 4693 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.408 AC: 1415 AN: 3472

East Asian (EAS) AF: 0.177 AC: 916 AN: 5178

South Asian (SAS) AF: 0.393 AC: 1894 AN: 4822

European-Finnish (FIN) AF: 0.242 AC: 2562 AN: 10570

Middle Eastern (MID) AF: 0.432 AC: 127 AN: 294

European-Non Finnish (NFE) AF: 0.294 AC: 20001 AN: 67980

Other (OTH) AF: 0.348 AC: 736 AN: 2112

Alfa AF: 0.312 Hom.: 6011

Bravo AF: 0.347

TwinsUK AF: 0.292 AC: 1083

ALSPAC AF: 0.309 AC: 1192

ESP6500AA AF: 0.452 AC: 626

ESP6500EA AF: 0.301 AC: 958

ExAC AF: 0.338 AC: 7220

Asia WGS AF: 0.315 AC: 1097 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Platelet-type bleeding disorder 20 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.9
DANN	Benign	0.12
DEOGEN2	Benign	0.0012	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.00035	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.75
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.46	N
REVEL	Benign	0.011
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.028
ClinPred		0.00029	T
GERP RS		2.8
Varity_R		0.060
gMVP		0.089
Mutation Taster		=100/0	polymorphism (auto)

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: rs8073060; hg19: chr17-33875262; COSMIC: COSV70570257; COSMIC: COSV70570257;