Genetic Variant NM_001127496.3:c.766G>A (chr5-142314343-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_001127496.3(SPRY4):c.766G>A(p.Gly256Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,461,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

SPRY4
NM_001127496.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.57

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]

SPRY4 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.928

BS2

High AC in GnomAdExome4 at 16 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPRY4	NM_001127496.3 link	c.766G>A	p.Gly256Ser	missense_variant	Exon 2 of 2	ENST00000434127.3	NP_001120968.1	Q9C004-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SPRY4	ENST00000434127.3 link	c.766G>A	p.Gly256Ser	missense_variant	Exon 2 of 2	1	NM_001127496.3	ENSP00000399468.2	Q9C004-1
SPRY4	ENST00000344120.4 link	c.835G>A	p.Gly279Ser	missense_variant	Exon 3 of 3	1		ENSP00000344967.4	A0A0C4DFS6
SPRY4	ENST00000643792.1 link	n.1448G>A		non_coding_transcript_exon_variant	Exon 1 of 1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250626

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135600

show subpopulations

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:

0.0000109

AC:

AN:

1461700

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727184

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000989

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000468

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hypogonadotropic hypogonadism 7 with or without anosmia;C3808971:Hypogonadotropic hypogonadism 17 with or without anosmia

Uncertain:1

Aug 23, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

T;D

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.97

D;D

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.93

D;D

MetaSVM

Uncertain

-0.0092

MutationAssessor

Pathogenic

3.0

.;M

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-5.1

D;D

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.010

D;D

Polyphen

1.0

.;D

Vest4

0.89

MutPred

0.80

.;Loss of methylation at K259 (P = 0.1);

MVP

0.95

MPC

1.1

ClinPred

0.99

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.90

gMVP

0.70

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over