5-142314222-T-TCGGGCCTGCTGGTCTTGG

Position:

• chr5-142314222-T-TCGGGCCTGCTGGTCTTGG

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM4 BS2

The NM_001127496.3(SPRY4):​c.869_886dupCCAAGACCAGCAGGCCCG​(p.Ala290_Pro295dup) variant causes a conservative inframe insertion change. The variant allele was found at a frequency of 0.00000343 in 1,455,896 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SPRY4 NM_001127496.3 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.71

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 Uncertain_significance. Variant got 0 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
• PM4: Nonframeshift variant in NON repetitive region in NM_001127496.3.
• BS2: High AC in GnomAdExome4 at 5 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPRY4	NM_001127496.3	c.869_886dupCCAAGACCAGCAGGCCCG	p.Ala290_Pro295dup	conservative_inframe_insertion	2/2	ENST00000434127.3	NP_001120968.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPRY4	ENST00000434127.3	c.869_886dupCCAAGACCAGCAGGCCCG	p.Ala290_Pro295dup	conservative_inframe_insertion	2/2	1	NM_001127496.3	ENSP00000399468.2
SPRY4	ENST00000344120.4	c.938_955dupCCAAGACCAGCAGGCCCG	p.Ala313_Pro318dup	conservative_inframe_insertion	3/3	1		ENSP00000344967.4
SPRY4	ENST00000643792.1	n.1551_1568dupCCAAGACCAGCAGGCCCG		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1455896 Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 2 AN XY: 723852

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 10, 2024

This variant, c.938_955dup, results in the insertion of 6 amino acid(s) of the SPRY4 protein (p.Ala313_Pro318dup), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SPRY4-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1759040138; hg19: chr5-141693787;