5-142314455-GG-AT

Variant names:

• chr5-142314455-GG-AT
• NM_001127496.3:c.653_654delCCinsAT
• SPRY4 p.Ser218Tyr

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_001127496.3(SPRY4):​c.653_654delCCinsAT​(p.Ser218Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPRY4 NM_001127496.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.60
• 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: AD, Unknown Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• 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 1 ACMG points.

• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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.653_654delCCinsAT	p.Ser218Tyr	missense	N/A	NP_001120968.1	Q9C004-1
	SPRY4	NM_030964.5		c.722_723delCCinsAT	p.Ser241Tyr	missense	N/A	NP_112226.2
	SPRY4	NM_001293289.3		c.653_654delCCinsAT	p.Ser218Tyr	missense	N/A	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.653_654delCCinsAT	p.Ser218Tyr	missense	N/A	ENSP00000399468.2	Q9C004-1
	SPRY4	ENST00000344120.4	TSL:1	c.722_723delCCinsAT	p.Ser241Tyr	missense	N/A	ENSP00000344967.4	A0A0C4DFS6
	SPRY4	ENST00000889413.1		c.653_654delCCinsAT	p.Ser218Tyr	missense	N/A	ENSP00000559472.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.6

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr5-141694020;