10-121564448-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000141.5(FGFR2):​c.454+54T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0268 in 1,521,000 control chromosomes in the GnomAD database, including 5,241 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 2639 hom., cov: 32)
Exomes 𝑓: 0.018 ( 2602 hom. )

Consequence

FGFR2
NM_000141.5 intron

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.229
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 Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.9).
BP6
Variant 10-121564448-A-G is Benign according to our data. Variant chr10-121564448-A-G is described in ClinVar as [Benign]. Clinvar id is 1221381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.341 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
FGFR2NM_000141.5 linkuse as main transcriptc.454+54T>C intron_variant ENST00000358487.10
FGFR2NM_022970.4 linkuse as main transcriptc.454+54T>C intron_variant ENST00000457416.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
FGFR2ENST00000358487.10 linkuse as main transcriptc.454+54T>C intron_variant 1 NM_000141.5 A2P21802-1
FGFR2ENST00000457416.7 linkuse as main transcriptc.454+54T>C intron_variant 1 NM_022970.4 P4P21802-3

Frequencies

GnomAD3 genomes
AF:
0.110
AC:
16661
AN:
151838
Hom.:
2621
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.345
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0873
Gnomad ASJ
AF:
0.000864
Gnomad EAS
AF:
0.0734
Gnomad SAS
AF:
0.00752
Gnomad FIN
AF:
0.0302
Gnomad MID
AF:
0.00949
Gnomad NFE
AF:
0.00262
Gnomad OTH
AF:
0.0822
GnomAD4 exome
AF:
0.0175
AC:
24014
AN:
1369042
Hom.:
2602
Cov.:
22
AF XY:
0.0154
AC XY:
10543
AN XY:
686418
show subpopulations
Gnomad4 AFR exome
AF:
0.358
Gnomad4 AMR exome
AF:
0.106
Gnomad4 ASJ exome
AF:
0.000702
Gnomad4 EAS exome
AF:
0.0729
Gnomad4 SAS exome
AF:
0.00344
Gnomad4 FIN exome
AF:
0.0288
Gnomad4 NFE exome
AF:
0.00132
Gnomad4 OTH exome
AF:
0.0324
GnomAD4 genome
AF:
0.110
AC:
16727
AN:
151958
Hom.:
2639
Cov.:
32
AF XY:
0.109
AC XY:
8132
AN XY:
74274
show subpopulations
Gnomad4 AFR
AF:
0.346
Gnomad4 AMR
AF:
0.0880
Gnomad4 ASJ
AF:
0.000864
Gnomad4 EAS
AF:
0.0726
Gnomad4 SAS
AF:
0.00753
Gnomad4 FIN
AF:
0.0302
Gnomad4 NFE
AF:
0.00262
Gnomad4 OTH
AF:
0.0818
Alfa
AF:
0.0464
Hom.:
207
Bravo
AF:
0.126
Asia WGS
AF:
0.0570
AC:
199
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Benign, criteria provided, single submitterclinical testingGeneDxJun 25, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.90
CADD
Benign
9.7
DANN
Benign
0.63

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

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

Other links and lift over

dbSNP: rs2303568; hg19: chr10-123323962; COSMIC: COSV60642648; API