5-142314648-T-A

Variant names:

• chr5-142314648-T-A
• rs78310959
• NM_001127496.3:c.461A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001127496.3(SPRY4):​c.461A>T​(p.Lys154Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. K154R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPRY4 NM_001127496.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.64
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• hypogonadotropic hypogonadism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Kallmann syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hypogonadotropic hypogonadism 17 with or without anosmia

  Inheritance: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPRY4	NM_001127496.3	c.461A>T	p.Lys154Met	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.461A>T	p.Lys154Met	missense_variant	Exon 2 of 2	1	NM_001127496.3	ENSP00000399468.2
SPRY4	ENST00000344120.4	c.530A>T	p.Lys177Met	missense_variant	Exon 3 of 3	1		ENSP00000344967.4
SPRY4	ENST00000643792.1	n.1143A>T		non_coding_transcript_exon_variant	Exon 1 of 1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.012	T;T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.050	D
MetaRNN	Uncertain	0.50	T;T
MetaSVM	Benign	-0.39	T
MutationAssessor	Uncertain	2.4	.;M
PhyloP100		7.6
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	0.0	N;N
REVEL	Uncertain	0.32
Sift	Benign	0.064	T;D
Sift4G	Benign	0.13	T;T
Polyphen		1.0	.;D
Vest4		0.55
MutPred		0.34		.;Loss of ubiquitination at K154 (P = 0.0043);
MVP		0.92
MPC		1.3
ClinPred		0.94	D
GERP RS		4.4
Varity_R		0.29
gMVP		0.52
Mutation Taster		=44/56	disease causing

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

Other links and lift over

dbSNP: rs78310959; hg19: chr5-141694213;