10-121517460-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 5P and 7B. PM1 PM5 PP2 BP4 BP6_Moderate BS2

The NM_000141.5(FGFR2):c.943G>A(p.Ala315Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,972 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 Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A315S) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: FGFR2 NM_000141.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B: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 Likely_benign. Variant got -2 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 2 uncertain in NM_000141.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-121517460-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 13289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, FGFR2
• BP4: Computational evidence support a benign effect (MetaRNN=0.41775393).
• BP6: Variant 10-121517460-C-T is Benign according to our data. Variant chr10-121517460-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3064171.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGFR2	NM_000141.5	c.943G>A	p.Ala315Thr	missense_variant	8/18	ENST00000358487.10
FGFR2	NM_022970.4	c.1087+1222G>A		intron_variant		ENST00000457416.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGFR2	ENST00000358487.10	c.943G>A	p.Ala315Thr	missense_variant	8/18	1	NM_000141.5	A2
FGFR2	ENST00000457416.7	c.1087+1222G>A		intron_variant		1	NM_022970.4	P4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152110 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251394 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135870

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461862 Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11 AN XY: 727228

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152110 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74312

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pfeiffer syndrome Benign:1

Likely benign, criteria provided, single submitter

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 17, 2024

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Uncertain	-0.020
Cadd	Pathogenic	27
Dann	Uncertain	1.0
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;T;D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.42	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.51	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	0.34
Sift	Benign	0.12	T;.;T;.;T;T;.;T
Sift4G	Benign	0.17	T;T;T;T;T;T;T;.
Polyphen		0.045	B;.;.;.;B;.;.;.
Vest4		0.75
MVP		0.73
ClinPred		0.16	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.42

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: rs121918504; hg19: chr10-123276974; COSMIC: COSV60645182; COSMIC: COSV60645182;