NM_000141.5:c.1084_1084+1insTCAACA

Variant names:

• chr10-121517318-C-CTGTTGA
• rs1554928786
• NM_000141.5:c.1084_1084+1insTCAACA

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM4 PP3

The NM_000141.5(FGFR2):​c.1084_1084+1insTCAACA​(p.Ala362delinsValAsnThr) variant causes a conservative inframe insertion, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FGFR2 NM_000141.5 conservative_inframe_insertion, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.85

Genes affected

FGFR2 (HGNC:3689): (fibroblast growth factor receptor 2) The protein encoded by this gene is a member of the fibroblast growth factor receptor family, where amino acid sequence is highly conserved between members and throughout evolution. FGFR family members differ from one another in their ligand affinities and tissue distribution. A full-length representative protein consists of an extracellular region, composed of three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment and a cytoplasmic tyrosine kinase domain. The extracellular portion of the protein interacts with fibroblast growth factors, setting in motion a cascade of downstream signals, ultimately influencing mitogenesis and differentiation. This particular family member is a high-affinity receptor for acidic, basic and/or keratinocyte growth factor, depending on the isoform. Mutations in this gene are associated with Crouzon syndrome, Pfeiffer syndrome, Craniosynostosis, Apert syndrome, Jackson-Weiss syndrome, Beare-Stevenson cutis gyrata syndrome, Saethre-Chotzen syndrome, and syndromic craniosynostosis. Multiple alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Jan 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000141.5.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.1084_1084+1insTCAACA	p.Ala362delinsValAsnThr	conservative_inframe_insertion, splice_region_variant	Exon 8 of 18	ENST00000358487.10	NP_000132.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000358487.10	c.1084_1084+1insTCAACA	p.Ala362delinsValAsnThr	conservative_inframe_insertion, splice_region_variant	Exon 8 of 18	1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000613048.4	c.817_817+1insTCAACA	p.Ala273delinsValAsnThr	conservative_inframe_insertion, splice_region_variant	Exon 7 of 17	5		ENSP00000484154.1
FGFR2	ENST00000478859.5	c.400_400+1insTCAACA	p.Ala134delinsValAsnThr	conservative_inframe_insertion, splice_region_variant	Exon 7 of 17	1		ENSP00000474011.1
FGFR2	ENST00000457416.7	c.1087+1363_1087+1364insTCAACA		intron_variant	Intron 8 of 17	1		ENSP00000410294.2
FGFR2	ENST00000369056.5	c.1087+1363_1087+1364insTCAACA		intron_variant	Intron 7 of 16	1		ENSP00000358052.1
FGFR2	ENST00000369058.7	c.1087+1363_1087+1364insTCAACA		intron_variant	Intron 8 of 16	1		ENSP00000358054.3
FGFR2	ENST00000369061.8	c.749-2000_749-1999insTCAACA		intron_variant	Intron 5 of 14	1		ENSP00000358057.4
FGFR2	ENST00000369059.5	c.742+1363_742+1364insTCAACA		intron_variant	Intron 6 of 15	5		ENSP00000358055.1
FGFR2	ENST00000360144.7	c.820+1363_820+1364insTCAACA		intron_variant	Intron 7 of 16	2		ENSP00000353262.3
FGFR2	ENST00000604236.5	n.*131_*131+1insTCAACA		splice_region_variant, non_coding_transcript_exon_variant	Exon 7 of 17	1		ENSP00000474109.1
FGFR2	ENST00000604236.5	n.*131_*131+1insTCAACA		3_prime_UTR_variant	Exon 7 of 17	1		ENSP00000474109.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

FGFR2-related craniosynostosis Uncertain:1

Nov 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.1084_1084+1insTCAACA, results in the deletion of 1 amino acid and insertion of 3 amino acid(s) of the FGFR2 protein (p.Ala362delinsValAsnThr), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with FGFR2-related conditions (PMID: 8644708; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 544300). Studies have shown that this variant is associated with inconclusive levels of altered splicing (PMID: 8644708). 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: rs1554928786; hg19: chr10-123276832;