rs201009569

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001127496.3(SPRY4):​c.727G>C​(p.Val243Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. V243M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

SPRY4
NM_001127496.3 missense

Scores

19

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0860
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 Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.059882134).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SPRY4NM_001127496.3 linkc.727G>C p.Val243Leu missense_variant Exon 2 of 2 ENST00000434127.3 NP_001120968.1 Q9C004-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SPRY4ENST00000434127.3 linkc.727G>C p.Val243Leu missense_variant Exon 2 of 2 1 NM_001127496.3 ENSP00000399468.2 Q9C004-1
SPRY4ENST00000344120.4 linkc.796G>C p.Val266Leu missense_variant Exon 3 of 3 1 ENSP00000344967.4 A0A0C4DFS6
SPRY4ENST00000643792.1 linkn.1409G>C non_coding_transcript_exon_variant Exon 1 of 1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461646
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
727114
show subpopulations
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.061
BayesDel_addAF
Benign
-0.29
T
BayesDel_noAF
Benign
-0.66
CADD
Benign
1.4
DANN
Benign
0.83
DEOGEN2
Benign
0.0094
T;T
Eigen
Benign
-1.4
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.037
N
LIST_S2
Benign
0.84
T;T
M_CAP
Benign
0.0043
T
MetaRNN
Benign
0.060
T;T
MetaSVM
Benign
-0.98
T
MutationAssessor
Benign
-1.3
.;N
PrimateAI
Benign
0.35
T
PROVEAN
Benign
1.1
N;N
REVEL
Benign
0.15
Sift
Benign
1.0
T;T
Sift4G
Benign
1.0
T;T
Polyphen
0.0
.;B
Vest4
0.061
MutPred
0.45
.;Loss of helix (P = 0.079);
MVP
0.39
MPC
0.34
ClinPred
0.082
T
GERP RS
-1.5
Varity_R
0.044
gMVP
0.18

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-141693947; API