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rs121918492

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP2PP3_Moderate

The NM_000141.5(FGFR2):​c.1031C>T​(p.Ala344Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A344G) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

FGFR2
NM_000141.5 missense

Scores

4
6
6

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.93
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1
?
    PM1 - Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation
In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000141.5
PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PM5
?
    PM5 - Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before
Other missense variant is known to change same aminoacid residue: Variant chr10-121517372-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 13269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP2
?
    PP2 - Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease
Missense variant where missense usually causes diseases, FGFR2
PP3
?
    PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
FGFR2NM_000141.5 linkuse as main transcriptc.1031C>T p.Ala344Val missense_variant 8/18 ENST00000358487.10
FGFR2NM_022970.4 linkuse as main transcriptc.1087+1310C>T intron_variant ENST00000457416.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
FGFR2ENST00000358487.10 linkuse as main transcriptc.1031C>T p.Ala344Val missense_variant 8/181 NM_000141.5 A2P21802-1
FGFR2ENST00000457416.7 linkuse as main transcriptc.1087+1310C>T intron_variant 1 NM_022970.4 P4P21802-3

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461838
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
2
AN XY:
727224
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:
0.00000360
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.91
BayesDel_addAF
Pathogenic
0.34
D
BayesDel_noAF
Pathogenic
0.25
CADD
Pathogenic
34
DANN
Uncertain
1.0
Eigen
Uncertain
0.44
Eigen_PC
Uncertain
0.58
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.95
D;D;D;D;D;D;D;D
M_CAP
Benign
0.013
T
MetaRNN
Uncertain
0.74
D;D;D;D;D;D;D;D
MetaSVM
Benign
-0.57
T
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D;D;D
PROVEAN
Benign
-2.1
N;.;N;.;N;N;.;N
REVEL
Uncertain
0.45
Sift
Benign
0.25
T;.;T;.;T;T;.;T
Sift4G
Benign
0.15
T;T;T;T;T;T;T;.
Polyphen
0.60
P;.;.;.;B;.;.;.
Vest4
0.96
MutPred
0.64
.;.;Gain of sheet (P = 0.0344);.;.;Gain of sheet (P = 0.0344);.;.;
MVP
0.94
ClinPred
0.90
D
GERP RS
5.9
Varity_R
0.43

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.82
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.82
Position offset: 2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-123276886; API