chr5-142314456-G-T
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_001127496.3(SPRY4):c.653C>A(p.Ser218Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00625 in 1,614,168 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0043 ( 3 hom., cov: 32)
Exomes 𝑓: 0.0065 ( 34 hom. )
Consequence
SPRY4
NM_001127496.3 missense
NM_001127496.3 missense
Scores
2
10
6
Clinical Significance
Conservation
PhyloP100: 9.60
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 -9 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.013144106).
BP6
?
Variant 5-142314456-G-T is Benign according to our data. Variant chr5-142314456-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 50874.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.
BS2
?
High AC in GnomAd at 653 AD,Digenic gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SPRY4 | NM_001127496.3 | c.653C>A | p.Ser218Tyr | missense_variant | 2/2 | ENST00000434127.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SPRY4 | ENST00000434127.3 | c.653C>A | p.Ser218Tyr | missense_variant | 2/2 | 1 | NM_001127496.3 | P1 | |
SPRY4 | ENST00000344120.4 | c.722C>A | p.Ser241Tyr | missense_variant | 3/3 | 1 | |||
SPRY4 | ENST00000643792.1 | n.1335C>A | non_coding_transcript_exon_variant | 1/1 |
Frequencies
GnomAD3 genomes ? AF: 0.00429 AC: 653AN: 152188Hom.: 3 Cov.: 32
GnomAD3 genomes
?
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GnomAD3 exomes AF: 0.00446 AC: 1119AN: 250986Hom.: 4 AF XY: 0.00431 AC XY: 585AN XY: 135686
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GnomAD4 exome AF: 0.00645 AC: 9436AN: 1461862Hom.: 34 Cov.: 32 AF XY: 0.00628 AC XY: 4568AN XY: 727226
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GnomAD4 genome ? AF: 0.00429 AC: 653AN: 152306Hom.: 3 Cov.: 32 AF XY: 0.00403 AC XY: 300AN XY: 74470
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:3Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:3
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2023 | SPRY4: BS2 - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 26, 2020 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31726455, 23643382) - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 29, 2016 | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in individuals with Kallman syndrome and controls was the same (Miraoui 2013). - |
Amenorrhea Uncertain:1
Uncertain significance, no assertion criteria provided | literature only | Yale Center for Mendelian Genomics, Yale University | Mar 08, 2021 | - - |
Hypogonadotropic hypogonadism 17 with or without anosmia Other:1
risk factor, no assertion criteria provided | literature only | OMIM | May 02, 2013 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Benign
T;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
T
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
1.0
.;D
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at