rs121918503

Variant names:

• chr10-121520097-ACGT-A
• rs121918503
• NM_000141.5:c.818_820delACG

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM4_Supporting PP5

The NM_000141.5(FGFR2):​c.818_820delACG​(p.Asp273del) variant causes a disruptive inframe deletion 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FGFR2 NM_000141.5 disruptive_inframe_deletion
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.01

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a domain Ig-like C2-type 3 (size 102) in uniprot entity FGFR2_HUMAN there are 48 pathogenic changes around while only 2 benign (96%) in NM_000141.5
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000141.5. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 10-121520097-ACGT-A is Pathogenic according to our data. Variant chr10-121520097-ACGT-A is described in ClinVar as [Pathogenic]. Clinvar id is 13288.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.818_820delACG	p.Asp273del	disruptive_inframe_deletion	Exon 7 of 18	ENST00000358487.10	NP_000132.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000358487.10	c.818_820delACG	p.Asp273del	disruptive_inframe_deletion	Exon 7 of 18	1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000457416.7	c.818_820delACG	p.Asp273del	disruptive_inframe_deletion	Exon 7 of 18	1		ENSP00000410294.2
FGFR2	ENST00000369056.5	c.818_820delACG	p.Asp273del	disruptive_inframe_deletion	Exon 6 of 17	1		ENSP00000358052.1
FGFR2	ENST00000369058.7	c.818_820delACG	p.Asp273del	disruptive_inframe_deletion	Exon 7 of 17	1		ENSP00000358054.3
FGFR2	ENST00000613048.4	c.551_553delACG	p.Asp184del	disruptive_inframe_deletion	Exon 6 of 17	5		ENSP00000484154.1
FGFR2	ENST00000369059.5	c.473_475delACG	p.Asp158del	disruptive_inframe_deletion	Exon 5 of 16	5		ENSP00000358055.1
FGFR2	ENST00000360144.7	c.551_553delACG	p.Asp184del	disruptive_inframe_deletion	Exon 6 of 17	2		ENSP00000353262.3
FGFR2	ENST00000478859.5	c.134_136delACG	p.Asp45del	disruptive_inframe_deletion	Exon 6 of 17	1		ENSP00000474011.1
FGFR2	ENST00000369061.8	c.749-4781_749-4779delACG		intron_variant	Intron 5 of 14	1		ENSP00000358057.4
FGFR2	ENST00000604236.5	n.473_475delACG		non_coding_transcript_exon_variant	Exon 5 of 17	1		ENSP00000474109.1

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Pfeiffer syndrome Pathogenic:1

Jul 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs121918503; hg19: chr10-123279611;