Genetic Variant SPRYD3:p.Arg227Ser (chr12-53073298-T-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_032840.3(SPRYD3):c.681A>T(p.Arg227Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000458 in 763,936 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.

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., cov: 26)

Exomes 𝑓: 0.000052 ( 0 hom. )

Consequence

SPRYD3
NM_032840.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.130

Variant links:

Genes affected

SPRYD3 (HGNC:25920): (SPRY domain containing 3) Predicted to be involved in cell surface receptor signaling pathway and cytoskeleton organization. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

SPRYD3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAdExome4 at 34 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPRYD3	NM_032840.3 link	c.681A>T	p.Arg227Ser	missense_variant	Exon 6 of 11	ENST00000301463.9	NP_116229.1	Q8NCJ5A0A024RAX4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPRYD3	ENST00000301463.9 link	c.681A>T	p.Arg227Ser	missense_variant	Exon 6 of 11	1	NM_032840.3	ENSP00000301463.4		Q8NCJ5

Frequencies

GnomAD3 genomes

AF:

0.00000898

AC:

AN:

111320

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000168

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000406

AC:

AN:

196932

Hom.:

AF XY:

0.0000381

AC XY:

AN XY:

104894

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000343

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000116

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000521

AC:

AN:

652616

Hom.:

Cov.:

AF XY:

0.0000574

AC XY:

AN XY:

331028

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000477

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000266

Gnomad4 NFE exome

AF:

0.0000331

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.00000898

AC:

AN:

111320

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

50498

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000168

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000331

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 23, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.681A>T (p.R227S) alteration is located in exon 6 (coding exon 6) of the SPRYD3 gene. This alteration results from a A to T substitution at nucleotide position 681, causing the arginine (R) at amino acid position 227 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Uncertain

0.083

BayesDel_noAF

Benign

-0.12

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.013

T;T

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.28

LIST_S2

Uncertain

0.97

D;D

M_CAP

Benign

0.0058

MetaRNN

Benign

0.034

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

M;.

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-1.0

N;N

REVEL

Benign

0.18

Sift

Benign

0.18

T;T

Sift4G

Uncertain

0.034

D;D

Polyphen

0.030

B;.

Vest4

0.45

MutPred

0.48

Gain of catalytic residue at T231 (P = 0);.;

MVP

0.47

MPC

0.88

ClinPred

0.13

GERP RS

-1.9

Varity_R

0.15

gMVP

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.43

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.43

Position offset: 6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over