10-121478538-T-C

Variant names:

• chr10-121478538-T-C
• rs3135830
• NM_000141.5:c.*1319A>G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000141.5(FGFR2):​c.*1319A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0144 in 233,386 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.014 (20 hom., cov: 33)
  • Exomes 𝑓: 0.016 (15 hom.)
• Consequence: FGFR2 NM_000141.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, single submitter B:5
• Conservation: PhyloP100: -1.50

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 10-121478538-T-C is Benign according to our data. Variant chr10-121478538-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 298978.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0135 (2063/152302) while in subpopulation NFE AF= 0.0179 (1219/68026). AF 95% confidence interval is 0.0171. There are 20 homozygotes in gnomad4. There are 1034 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 20 Mitochondrial gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.*1319A>G		3_prime_UTR_variant	Exon 18 of 18	ENST00000358487.10	NP_000132.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000358487	c.*1319A>G		3_prime_UTR_variant	Exon 18 of 18	1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000457416	c.*1319A>G		3_prime_UTR_variant	Exon 18 of 18	1		ENSP00000410294.2
FGFR2	ENST00000613048	c.*1319A>G		3_prime_UTR_variant	Exon 17 of 17	5		ENSP00000484154.1
FGFR2	ENST00000369061	c.*1319A>G		3_prime_UTR_variant	Exon 15 of 15	1		ENSP00000358057.4
FGFR2	ENST00000478859	c.*1319A>G		3_prime_UTR_variant	Exon 17 of 17	1		ENSP00000474011.1

Frequencies

GnomAD3 genomes AF: 0.0135 AC: 2061 AN: 152184 Hom.: 20 Cov.: 33

Gnomad AFR AF: 0.00540

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00570

Gnomad ASJ AF: 0.0374

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0114

Gnomad FIN AF: 0.0292

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0179

Gnomad OTH AF: 0.0115

GnomAD4 exome AF: 0.0160 AC: 1294 AN: 81084 Hom.: 15 Cov.: 0 AF XY: 0.0168 AC XY: 626 AN XY: 37292

Gnomad4 AFR exome AF: 0.00590

Gnomad4 AMR exome AF: 0.00601

Gnomad4 ASJ exome AF: 0.0393

Gnomad4 EAS exome AF: 0.0000878

Gnomad4 SAS exome AF: 0.0143

Gnomad4 FIN exome AF: 0.0280

Gnomad4 NFE exome AF: 0.0181

Gnomad4 OTH exome AF: 0.0186

GnomAD4 genome AF: 0.0135 AC: 2063 AN: 152302 Hom.: 20 Cov.: 33 AF XY: 0.0139 AC XY: 1034 AN XY: 74474

Gnomad4 AFR AF: 0.00541

Gnomad4 AMR AF: 0.00569

Gnomad4 ASJ AF: 0.0374

Gnomad4 EAS AF: 0.00154

Gnomad4 SAS AF: 0.0114

Gnomad4 FIN AF: 0.0292

Gnomad4 NFE AF: 0.0179

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.0165 Hom.: 26

Bravo AF: 0.0113

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, single submitter

Submissions by phenotype

Crouzon syndrome Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Beare-Stevenson cutis gyrata syndrome Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Isolated Coronal Synostosis Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Craniosynostosis syndrome Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Saethre-Chotzen syndrome Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.030
DANN	Benign	0.44

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs3135830; hg19: chr10-123238052;