Genetic Variant SLFN14:p.Arg223Gly (chr17-35557396-G-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2PM5BP4

The NM_001129820.2(SLFN14):c.667C>G(p.Arg223Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,384 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R223W) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

SLFN14
NM_001129820.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.201

Publications

7 publications found

Variant links:

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

SLFN14 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-35557396-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 225536.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.38175917).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLFN14	NM_001129820.2 link	c.667C>G	p.Arg223Gly	missense_variant	Exon 3 of 6	ENST00000674182.1	NP_001123292.1	P0C7P3-1
SLFN14	XM_017024577.2 link	c.667C>G	p.Arg223Gly	missense_variant	Exon 3 of 6		XP_016880066.1	P0C7P3-1
SLFN14	XM_017024578.2 link	c.667C>G	p.Arg223Gly	missense_variant	Exon 2 of 5		XP_016880067.1	P0C7P3-1
SLFN14	XM_017024579.2 link	c.667C>G	p.Arg223Gly	missense_variant	Exon 2 of 5		XP_016880068.1	P0C7P3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLFN14	ENST00000674182.1 link	c.667C>G	p.Arg223Gly	missense_variant	Exon 3 of 6		NM_001129820.2	ENSP00000501524.1		P0C7P3-1
SLFN14	ENST00000415846.3 link	c.667C>G	p.Arg223Gly	missense_variant	Exon 1 of 4	1		ENSP00000391101.2		P0C7P3-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000650

AC:

AN:

153960

AF XY:

0.0000122

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000168

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.15e-7

AC:

AN:

1399384

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

690198

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31596

American (AMR)

AF:

0.00

AC:

AN:

35702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25182

East Asian (EAS)

AF:

0.00

AC:

AN:

35736

South Asian (SAS)

AF:

0.00

AC:

AN:

79230

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49276

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

9.27e-7

AC:

AN:

1078966

Other (OTH)

AF:

0.00

AC:

AN:

57998

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Benign

-0.026

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.029

Eigen

Benign

-0.096

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.77

M_CAP

Benign

0.013

MetaRNN

Benign

0.38

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.4

PhyloP100

-0.20

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.26

Sift

Benign

0.40

Sift4G

Benign

0.40

Polyphen

1.0

Vest4

0.56

MutPred

0.46

Loss of MoRF binding (P = 0.0101);

MVP

0.26

ClinPred

0.44

GERP RS

1.1

Varity_R

0.15

gMVP

0.69

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over