NM_001127496.3:c.820C>T

Variant names:

• chr5-142314289-G-A
• rs568658303
• NM_001127496.3:c.820C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_001127496.3(SPRY4):​c.820C>T​(p.Arg274Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000136 in 1,613,760 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R274S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: SPRY4 NM_001127496.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.19
• Publications: 1 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 17 with or without anosmia

  Inheritance: Unknown, AD Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics
• hypogonadotropic hypogonadism

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.856
• BS2: High AC in GnomAdExome4 at 19 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127496.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPRY4	NM_001127496.3	MANE Select	c.820C>T	p.Arg274Cys	missense	Exon 2 of 2	NP_001120968.1	Q9C004-1
	SPRY4	NM_030964.5		c.889C>T	p.Arg297Cys	missense	Exon 3 of 3	NP_112226.2
	SPRY4	NM_001293289.3		c.820C>T	p.Arg274Cys	missense	Exon 3 of 3	NP_001280218.1	Q9C004-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPRY4	ENST00000434127.3	TSL:1 MANE Select	c.820C>T	p.Arg274Cys	missense	Exon 2 of 2	ENSP00000399468.2	Q9C004-1
	SPRY4	ENST00000344120.4	TSL:1	c.889C>T	p.Arg297Cys	missense	Exon 3 of 3	ENSP00000344967.4	A0A0C4DFS6
	SPRY4	ENST00000889413.1		c.820C>T	p.Arg274Cys	missense	Exon 3 of 3	ENSP00000559472.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152222 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250444 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461420 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10 AN XY: 727050

African (AFR) AF: 0.0000896 AC: 3 AN: 33476

American (AMR) AF: 0.0000224 AC: 1 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53092

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111942

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152340 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74480

African (AFR) AF: 0.00 AC: 0 AN: 41584

American (AMR) AF: 0.00 AC: 0 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.41	T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.094	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		6.2
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-7.2	D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.75
MVP		0.93
MPC		1.3
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.82
gMVP		0.69
Mutation Taster		=25/75	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: rs568658303; hg19: chr5-141693854;