5-142314223-C-G

Variant names:

• chr5-142314223-C-G
• rs771409068
• NM_001127496.3:c.886G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001127496.3(SPRY4):​c.886G>C​(p.Asp296His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 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. D296N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPRY4 NM_001127496.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.71
• 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 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21453041).

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.886G>C	p.Asp296His	missense	Exon 2 of 2	NP_001120968.1	Q9C004-1
	SPRY4	NM_030964.5		c.955G>C	p.Asp319His	missense	Exon 3 of 3	NP_112226.2
	SPRY4	NM_001293289.3		c.886G>C	p.Asp296His	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.886G>C	p.Asp296His	missense	Exon 2 of 2	ENSP00000399468.2	Q9C004-1
	SPRY4	ENST00000344120.4	TSL:1	c.955G>C	p.Asp319His	missense	Exon 3 of 3	ENSP00000344967.4	A0A0C4DFS6
	SPRY4	ENST00000889413.1		c.886G>C	p.Asp296His	missense	Exon 3 of 3	ENSP00000559472.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.027	T
Eigen	Benign	0.056
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.69	N
PhyloP100		5.7
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.12
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.026	D
Polyphen		0.61	P
Vest4		0.20
MutPred		0.13		Loss of solvent accessibility (P = 0.0117)
MVP		0.78
MPC		1.1
ClinPred		0.86	D
GERP RS		4.8
Varity_R		0.15
gMVP		0.42
Mutation Taster		=74/26	polymorphism

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: rs771409068; hg19: chr5-141693788;