rs504122

Positions:

• chr13-80337390-G-A
• chr13-80337390-G-C
• chr13-80337390-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005842.4(SPRY2):​c.316C>T​(p.Pro106Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.353 in 1,613,932 control chromosomes in the GnomAD database, including 105,010 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.29 (7776 hom., cov: 32)
  • Exomes 𝑓: 0.36 (97234 hom.)
• Consequence: SPRY2 NM_005842.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.01

Genes affected

SPRY2 (HGNC:11270): (sprouty RTK signaling antagonist 2) This gene encodes a protein belonging to the sprouty family. The encoded protein contains a carboxyl-terminal cysteine-rich domain essential for the inhibitory activity on receptor tyrosine kinase signaling proteins and is required for growth factor stimulated translocation of the protein to membrane ruffles. In primary dermal endothelial cells this gene is transiently upregulated in response to fibroblast growth factor two. This protein is indirectly involved in the non-cell autonomous inhibitory effect on fibroblast growth factor two signaling. The protein interacts with Cas-Br-M (murine) ectropic retroviral transforming sequence, and can function as a bimodal regulator of epidermal growth factor receptor/mitogen-activated protein kinase signaling. This protein may play a role in alveoli branching during lung development as shown by a similar mouse protein. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014727116).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.436 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPRY2	NM_005842.4	c.316C>T	p.Pro106Ser	missense_variant	2/2	ENST00000377104.4	NP_005833.1
SPRY2	NM_001318536.1	c.316C>T	p.Pro106Ser	missense_variant	2/2		NP_001305465.1
SPRY2	NM_001318537.1	c.316C>T	p.Pro106Ser	missense_variant	2/2		NP_001305466.1
SPRY2	NM_001318538.1	c.316C>T	p.Pro106Ser	missense_variant	2/2		NP_001305467.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPRY2	ENST00000377104.4	c.316C>T	p.Pro106Ser	missense_variant	2/2	1	NM_005842.4	ENSP00000366308.3
SPRY2	ENST00000377102.5	c.316C>T	p.Pro106Ser	missense_variant	2/2	1		ENSP00000366306.1

Frequencies

GnomAD3 genomes AF: 0.289 AC: 43850 AN: 151966 Hom.: 7763 Cov.: 32

Gnomad AFR AF: 0.0703

Gnomad AMI AF: 0.390

Gnomad AMR AF: 0.423

Gnomad ASJ AF: 0.329

Gnomad EAS AF: 0.451

Gnomad SAS AF: 0.335

Gnomad FIN AF: 0.373

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.358

Gnomad OTH AF: 0.326

GnomAD3 exomes AF: 0.367 AC: 92225 AN: 251408 Hom.: 18303 AF XY: 0.366 AC XY: 49712 AN XY: 135886

Gnomad AFR exome AF: 0.0660

Gnomad AMR exome AF: 0.520

Gnomad ASJ exome AF: 0.316

Gnomad EAS exome AF: 0.472

Gnomad SAS exome AF: 0.355

Gnomad FIN exome AF: 0.370

Gnomad NFE exome AF: 0.353

Gnomad OTH exome AF: 0.370

GnomAD4 exome AF: 0.360 AC: 525742 AN: 1461848 Hom.: 97234 Cov.: 64 AF XY: 0.359 AC XY: 261340 AN XY: 727230

Gnomad4 AFR exome AF: 0.0565

Gnomad4 AMR exome AF: 0.511

Gnomad4 ASJ exome AF: 0.321

Gnomad4 EAS exome AF: 0.423

Gnomad4 SAS exome AF: 0.357

Gnomad4 FIN exome AF: 0.359

Gnomad4 NFE exome AF: 0.362

Gnomad4 OTH exome AF: 0.357

GnomAD4 genome AF: 0.289 AC: 43878 AN: 152084 Hom.: 7776 Cov.: 32 AF XY: 0.294 AC XY: 21843 AN XY: 74322

Gnomad4 AFR AF: 0.0701

Gnomad4 AMR AF: 0.424

Gnomad4 ASJ AF: 0.329

Gnomad4 EAS AF: 0.451

Gnomad4 SAS AF: 0.339

Gnomad4 FIN AF: 0.373

Gnomad4 NFE AF: 0.358

Gnomad4 OTH AF: 0.323

Alfa AF: 0.344 Hom.: 18331

Bravo AF: 0.286

TwinsUK AF: 0.359 AC: 1331

ALSPAC AF: 0.354 AC: 1366

ESP6500AA AF: 0.0803 AC: 354

ESP6500EA AF: 0.359 AC: 3087

ExAC AF: 0.354 AC: 42968

Asia WGS AF: 0.329 AC: 1146 AN: 3478

EpiCase AF: 0.346

EpiControl AF: 0.359

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	11
DANN	Benign	0.94
DEOGEN2	Benign	0.34	T;T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.55	.;T
MetaRNN	Benign	0.0015	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.6	L;L
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-2.3	N;N
REVEL	Benign	0.14
Sift	Benign	0.097	T;T
Sift4G	Benign	0.074	T;T
Polyphen		0.0	B;B
Vest4		0.072
MPC		0.47
ClinPred		0.0061	T
GERP RS		0.64
Varity_R		0.069
gMVP		0.45

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: rs504122; hg19: chr13-80911525; COSMIC: COSV65701301;