rs587776981

Positions:

• chr5-142315063-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PP5 BP4

The NM_001127496.3(SPRY4):​c.46G>A​(p.Val16Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPRY4 NM_001127496.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.31

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a chain Protein sprouty homolog 4 (size 298) in uniprot entity SPY4_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_001127496.3
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-142315063-C-T is Pathogenic according to our data. Variant chr5-142315063-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 50875.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.13434678). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPRY4	NM_001127496.3	c.46G>A	p.Val16Ile	missense_variant	2/2	ENST00000434127.3	NP_001120968.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPRY4	ENST00000434127.3	c.46G>A	p.Val16Ile	missense_variant	2/2	1	NM_001127496.3	ENSP00000399468.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hypogonadotropic hypogonadism 17 with or without anosmia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 02, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0097	T;T;.
Eigen	Benign	-0.22
Eigen_PC	Benign	0.014
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.70	T;T;T
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.85	.;L;.
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.14	N;N;N
REVEL	Benign	0.069
Sift	Benign	0.16	T;T;T
Sift4G	Benign	0.50	T;T;.
Polyphen		0.0020	.;B;.
Vest4		0.063
MutPred		0.16		.;Gain of catalytic residue at L21 (P = 0.0244);Gain of catalytic residue at L21 (P = 0.0244);
MVP		0.71
MPC		0.28
ClinPred		0.33	T
GERP RS		4.6
Varity_R		0.089
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs587776981; hg19: chr5-141694628;