chr13-80337377-G-C

Variant names:

• chr13-80337377-G-C
• rs748075874
• NM_005842.4:c.329C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005842.4(SPRY2):​c.329C>G​(p.Ser110Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,850 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SPRY2 NM_005842.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.34

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPRY2	NM_005842.4	c.329C>G	p.Ser110Cys	missense_variant	Exon 2 of 2	ENST00000377104.4	NP_005833.1
SPRY2	NM_001318536.1	c.329C>G	p.Ser110Cys	missense_variant	Exon 2 of 2		NP_001305465.1
SPRY2	NM_001318537.1	c.329C>G	p.Ser110Cys	missense_variant	Exon 2 of 2		NP_001305466.1
SPRY2	NM_001318538.1	c.329C>G	p.Ser110Cys	missense_variant	Exon 2 of 2		NP_001305467.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPRY2	ENST00000377104.4	c.329C>G	p.Ser110Cys	missense_variant	Exon 2 of 2	1	NM_005842.4	ENSP00000366308.3
SPRY2	ENST00000377102.5	c.329C>G	p.Ser110Cys	missense_variant	Exon 2 of 2	1		ENSP00000366306.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251468 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135906

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 SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461850 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 14, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.329C>G (p.S110C) alteration is located in exon 2 (coding exon 1) of the SPRY2 gene. This alteration results from a C to G substitution at nucleotide position 329, causing the serine (S) at amino acid position 110 to be replaced by a cysteine (C). 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	Benign	0.31
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	28
DANN	Benign	0.97
DEOGEN2	Benign	0.34	T;T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	.;D
M_CAP	Benign	0.033	D
MetaRNN	Uncertain	0.65	D;D
MetaSVM	Benign	-0.39	T
MutationAssessor	Uncertain	2.5	M;M
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Benign	0.21
Sift	Benign	0.030	D;D
Sift4G	Benign	0.080	T;T
Polyphen		1.0	D;D
Vest4		0.67
MutPred		0.35		Loss of phosphorylation at S110 (P = 0.0019);Loss of phosphorylation at S110 (P = 0.0019);
MVP		0.52
MPC		1.3
ClinPred		0.78	D
GERP RS		5.1
Varity_R		0.24
gMVP		0.67

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: rs748075874; hg19: chr13-80911512;