5-142314289-G-T

Variant names:

• chr5-142314289-G-T
• NM_001127496.3:c.820C>A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_001127496.3(SPRY4):​c.820C>A​(p.Arg274Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPRY4 NM_001127496.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 6.19

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPRY4	NM_001127496.3	c.820C>A	p.Arg274Ser	missense_variant	Exon 2 of 2	ENST00000434127.3	NP_001120968.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPRY4	ENST00000434127.3	c.820C>A	p.Arg274Ser	missense_variant	Exon 2 of 2	1	NM_001127496.3	ENSP00000399468.2
SPRY4	ENST00000344120.4	c.889C>A	p.Arg297Ser	missense_variant	Exon 3 of 3	1		ENSP00000344967.4
SPRY4	ENST00000643792.1	n.1502C>A		non_coding_transcript_exon_variant	Exon 1 of 1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

SPRY4-related disorder Uncertain:1

Aug 24, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SPRY4 c.889C>A variant is predicted to result in the amino acid substitution p.Arg297Ser. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T;D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.066	D
MutationAssessor	Pathogenic	3.2	.;M
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.4	D;D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.99	.;D
Vest4		0.87
MutPred		0.87		.;Loss of MoRF binding (P = 0.0159);
MVP		0.93
MPC		1.2
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.91
gMVP		0.74

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: chr5-141693854;