10-121482172-T-C

Variant names:

• chr10-121482172-T-C
• rs189179463
• ENST00000369056.5:c.2310A>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PM4 BS1_Supporting

The NM_001144913.1(FGFR2):​c.2310A>G​(p.Ter770Trpext*?) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000527 in 1,612,968 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 not provided (no stars).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: FGFR2 NM_001144913.1 stop_lost
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 0.0400

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_001144913.1 Downstream stopcodon found after 0 codons.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000263 (40/152266) while in subpopulation AFR AF= 0.000866 (36/41554). AF 95% confidence interval is 0.000642. There are 0 homozygotes in gnomad4. There are 18 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.2301+1526A>G		intron_variant	Intron 17 of 17	ENST00000358487.10	NP_000132.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000369056.5	c.2310A>G	p.Ter770Trpext*?	stop_lost	Exon 17 of 17	1		ENSP00000358052.1
FGFR2	ENST00000360144.7	c.2043A>G	p.Ter681Trpext*?	stop_lost	Exon 17 of 17	2		ENSP00000353262.3
FGFR2	ENST00000358487.10	c.2301+1526A>G		intron_variant	Intron 17 of 17	1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000457416.7	c.2304+1526A>G		intron_variant	Intron 17 of 17	1		ENSP00000410294.2
FGFR2	ENST00000613048.4	c.2034+1526A>G		intron_variant	Intron 16 of 16	5		ENSP00000484154.1
FGFR2	ENST00000369061.8	c.1965+1526A>G		intron_variant	Intron 14 of 14	1		ENSP00000358057.4
FGFR2	ENST00000369059.5	c.1959+1526A>G		intron_variant	Intron 15 of 15	5		ENSP00000358055.1
FGFR2	ENST00000478859.5	c.1617+1526A>G		intron_variant	Intron 16 of 16	1		ENSP00000474011.1
FGFR2	ENST00000429361.5	c.972-2151A>G		intron_variant	Intron 8 of 8	5		ENSP00000404219.1
FGFR2	ENST00000604236.5	n.*1348+1526A>G		intron_variant	Intron 16 of 16	1		ENSP00000474109.1

Frequencies

GnomAD3 genomes AF: 0.000269 AC: 41 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000612 AC: 15 AN: 245220 Hom.: 0 AF XY: 0.0000449 AC XY: 6 AN XY: 133512

Gnomad AFR exome AF: 0.000786

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: 0.0000273

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000308 AC: 45 AN: 1460702 Hom.: 0 Cov.: 29 AF XY: 0.0000303 AC XY: 22 AN XY: 726620

Gnomad4 AFR exome AF: 0.000926

Gnomad4 AMR exome AF: 0.0000448

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: 0.00000900

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152266 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74466

Gnomad4 AFR AF: 0.000866

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000348 Hom.: 0

Bravo AF: 0.000310

ESP6500AA AF: 0.00159 AC: 5

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000831 AC: 10

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not specified Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	17
DANN	Benign	0.82
Eigen	Benign	-0.057
Eigen_PC	Benign	-0.032
FATHMM_MKL	Benign	0.26	N
Vest4		0.16
GERP RS		3.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs189179463; hg19: chr10-123241686;