chr10-121517371-C-T

Position:

chr10-121517371-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_000141.5(FGFR2):c.1032G>A(p.Ala344Ala) variant causes a synonymous change. The variant allele was found at a frequency of 0.00000205 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

FGFR2
NM_000141.5 synonymous

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:15

Conservation

PhyloP100: 4.75

Variant links:

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]

FGFR2 links:

FGFR2 (HGNC:):

FGFR2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 10-121517371-C-T is Pathogenic according to our data. Variant chr10-121517371-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 13268.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-121517371-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR2	NM_000141.5 linkuse as main transcript	c.1032G>A	p.Ala344Ala	synonymous_variant	8/18	ENST00000358487.10	NP_000132.3	P21802-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
FGFR2	ENST00000358487.10 linkuse as main transcript	c.1032G>A	p.Ala344Ala	synonymous_variant	8/18	1	NM_000141.5	ENSP00000351276.6	P21802-1
FGFR2	ENST00000613048.4 linkuse as main transcript	c.765G>A	p.Ala255Ala	synonymous_variant	7/17	5		ENSP00000484154.1	D2CGD1
FGFR2	ENST00000478859.5 linkuse as main transcript	c.348G>A	p.Ala116Ala	synonymous_variant	7/17	1		ENSP00000474011.1	S4R381
FGFR2	ENST00000457416.7 linkuse as main transcript	c.1087+1311G>A		intron_variant		1		ENSP00000410294.2	P21802-3
FGFR2	ENST00000369056.5 linkuse as main transcript	c.1087+1311G>A		intron_variant		1		ENSP00000358052.1	P21802-17
FGFR2	ENST00000369058.7 linkuse as main transcript	c.1087+1311G>A		intron_variant		1		ENSP00000358054.3	A0A5S6RJB7
FGFR2	ENST00000369061.8 linkuse as main transcript	c.749-2052G>A		intron_variant		1		ENSP00000358057.4	P21802-23
FGFR2	ENST00000369059.5 linkuse as main transcript	c.742+1311G>A		intron_variant		5		ENSP00000358055.1	E7EVR7
FGFR2	ENST00000360144.7 linkuse as main transcript	c.820+1311G>A		intron_variant		2		ENSP00000353262.3	P21802-22
FGFR2	ENST00000604236.5 linkuse as main transcript	n.*79G>A		non_coding_transcript_exon_variant	7/17	1		ENSP00000474109.1	S4R3B2
FGFR2	ENST00000604236.5 linkuse as main transcript	n.*79G>A		3_prime_UTR_variant	7/17	1		ENSP00000474109.1	S4R3B2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251454

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461870

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727234

show subpopulations

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:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.000106

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Crouzon syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Sep 17, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Baylor Genetics	Nov 18, 2018	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 15, 2005	- -

not provided

Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 04, 2022	Published functional studies demonstrate abnormal gene splicing (Del Gatto et al., 1995; Li et al., 1995); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 7987400, 12400057, 15286168, 7773284, 16158432, 26841243, 25271085, 24127277, 30692697, 7558045, 11781872, 8957519) -

FGFR2-related craniosynostosis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

This sequence change affects codon 344 of the FGFR2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the FGFR2 protein. RNA analysis indicates that this variant induces altered splicing and likely results in the loss of 17 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs121918491, gnomAD 0.0009%). This variant has been observed in individuals with clinical features of Crouzon syndrome (PMID: 7987400, 8957519, 16838304). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13268). Studies have shown that this variant results in the activation of a cryptic splice site in exon 8 (PMID: 7773284). For these reasons, this variant has been classified as Pathogenic. -

FGFR2-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

May 06, 2022

PS3 PS4 PP1 -

Pfeiffer syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

3billion

May 22, 2022

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Functional studies provide supporting evidence of the variant having a damaging effect on the gene or gene product (PMID:7773284). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID:16418739, 16838304, 24127277, 8957519). The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000013268). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Acrocephalosyndactyly type I;C0010273:Crouzon syndrome;C0024623:Gastric cancer;C0175699:Saethre-Chotzen syndrome;C0220658:Pfeiffer syndrome;C0265269:Levy-Hollister syndrome;C0795998:Jackson-Weiss syndrome;C1852406:Beare-Stevenson cutis gyrata syndrome;C1865070:Familial scaphocephaly syndrome, McGillivray type;C2936791:Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis;C3281247:Bent bone dysplasia syndrome 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 17, 2021

- -

Scaphocephaly and axenfeld-rieger anomaly

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 15, 2005

- -

Craniosynostosis, nonclassifiable autosomal dominant

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 15, 2005

- -

Acrocephalosyndactyly type I;C0010273:Crouzon syndrome;C0038356:Neoplasm of stomach;C0175699:Saethre-Chotzen syndrome;C0220658:Pfeiffer syndrome;C0265269:Levy-Hollister syndrome;C0795998:Jackson-Weiss syndrome;C1852406:Beare-Stevenson cutis gyrata syndrome;C1865070:Familial scaphocephaly syndrome, McGillivray type;C2936791:Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis;C3281247:Bent bone dysplasia syndrome 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Craniosynostosis syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 20, 2015

- -

Acrocephalosyndactyly type I

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Benign

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.58

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.58

Position offset: -1

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over