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GeneBe

5-142314247-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001127496.3(SPRY4):c.862G>A(p.Gly288Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000347 in 1,612,134 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

SPRY4
NM_001127496.3 missense

Scores

2
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.04
Variant links:
Genes affected
SPRY4 (HGNC:15533): (sprouty RTK signaling antagonist 4) This gene encodes a member of a family of cysteine- and proline-rich proteins. The encoded protein is an inhibitor of the receptor-transduced mitogen-activated protein kinase (MAPK) signaling pathway. Activity of this protein impairs the formation of active GTP-RAS. Nucleotide variation in this gene has been associated with hypogonadotropic hypogonadism 17 with or without anosmia. Alternative splicing results in a multiple transcript variants. [provided by RefSeq, Jun 2014]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.058455408).
BS2
High AC in GnomAd at 16 AD,Digenic gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SPRY4NM_001127496.3 linkuse as main transcriptc.862G>A p.Gly288Arg missense_variant 2/2 ENST00000434127.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SPRY4ENST00000434127.3 linkuse as main transcriptc.862G>A p.Gly288Arg missense_variant 2/21 NM_001127496.3 P1Q9C004-1
SPRY4ENST00000344120.4 linkuse as main transcriptc.931G>A p.Gly311Arg missense_variant 3/31
SPRY4ENST00000643792.1 linkuse as main transcriptn.1544G>A non_coding_transcript_exon_variant 1/1

Frequencies

GnomAD3 genomes
AF:
0.000105
AC:
16
AN:
152220
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000362
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000242
AC:
6
AN:
248196
Hom.:
0
AF XY:
0.0000297
AC XY:
4
AN XY:
134576
show subpopulations
Gnomad AFR exome
AF:
0.000191
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000545
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:
0.0000274
AC:
40
AN:
1459914
Hom.:
0
Cov.:
32
AF XY:
0.0000303
AC XY:
22
AN XY:
726204
show subpopulations
Gnomad4 AFR exome
AF:
0.000478
Gnomad4 AMR exome
AF:
0.0000895
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000101
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000630
Gnomad4 OTH exome
AF:
0.0000828
GnomAD4 genome
AF:
0.000105
AC:
16
AN:
152220
Hom.:
0
Cov.:
32
AF XY:
0.0000672
AC XY:
5
AN XY:
74358
show subpopulations
Gnomad4 AFR
AF:
0.000362
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000230
Hom.:
0
Bravo
AF:
0.000144
ESP6500AA
AF:
0.000228
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 21, 2023The c.931G>A (p.G311R) alteration is located in exon 3 (coding exon 2) of the SPRY4 gene. This alteration results from a G to A substitution at nucleotide position 931, causing the glycine (G) at amino acid position 311 to be replaced by an arginine (R). 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
0.12
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Benign
-0.40
Cadd
Benign
15
Dann
Benign
0.96
DEOGEN2
Benign
0.059
T;T
Eigen
Benign
-0.91
Eigen_PC
Benign
-0.89
FATHMM_MKL
Benign
0.31
N
LIST_S2
Benign
0.75
T;T
M_CAP
Benign
0.015
T
MetaRNN
Benign
0.058
T;T
MetaSVM
Benign
-1.0
T
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.42
T
PROVEAN
Uncertain
-2.7
D;D
REVEL
Benign
0.050
Sift
Uncertain
0.021
D;T
Sift4G
Benign
0.14
T;T
Polyphen
0.18
.;B
Vest4
0.24
MutPred
0.22
.;Gain of solvent accessibility (P = 0.0023);
MVP
0.54
MPC
0.51
ClinPred
0.024
T
GERP RS
3.0
Varity_R
0.095
gMVP
0.38

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

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

Other links and lift over

dbSNP: rs148661341; hg19: chr5-141693812; API