10-121479454-T-C

Variant names:

• chr10-121479454-T-C
• rs3135826
• NM_000141.5:c.*403A>G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_000141.5(FGFR2):​c.*403A>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 0.02 in 455,472 control chromosomes in the GnomAD database, including 148 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (37 hom., cov: 33)
  • Exomes 𝑓: 0.022 (111 hom.)
• Consequence: FGFR2 NM_000141.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.30

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 10-121479454-T-C is Benign according to our data. Variant chr10-121479454-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 298989.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.016 (2437/152226) while in subpopulation NFE AF= 0.0267 (1814/68016). AF 95% confidence interval is 0.0256. There are 37 homozygotes in gnomad4. There are 1118 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 37 Mitochondrial gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.*403A>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.*403A>G		3_prime_UTR_variant	Exon 18 of 18	1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000457416	c.*403A>G		3_prime_UTR_variant	Exon 18 of 18	1		ENSP00000410294.2
FGFR2	ENST00000613048	c.*403A>G		3_prime_UTR_variant	Exon 17 of 17	5		ENSP00000484154.1
FGFR2	ENST00000369061	c.*403A>G		3_prime_UTR_variant	Exon 15 of 15	1		ENSP00000358057.4
FGFR2	ENST00000478859	c.*403A>G		3_prime_UTR_variant	Exon 17 of 17	1		ENSP00000474011.1
FGFR2	ENST00000604236.5	n.*1916A>G		non_coding_transcript_exon_variant	Exon 17 of 17	1		ENSP00000474109.1
FGFR2	ENST00000604236.5	n.*1916A>G		3_prime_UTR_variant	Exon 17 of 17	1		ENSP00000474109.1
FGFR2	ENST00000369059.5	c.*403A>G		downstream_gene_variant		5		ENSP00000358055.1

Frequencies

GnomAD3 genomes AF: 0.0160 AC: 2439 AN: 152110 Hom.: 37 Cov.: 33

Gnomad AFR AF: 0.00459

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.00904

Gnomad ASJ AF: 0.0233

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.0151

Gnomad FIN AF: 0.00539

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0267

Gnomad OTH AF: 0.0211

GnomAD4 exome AF: 0.0220 AC: 6668 AN: 303246 Hom.: 111 Cov.: 5 AF XY: 0.0226 AC XY: 3471 AN XY: 153868

Gnomad4 AFR exome AF: 0.00339

Gnomad4 AMR exome AF: 0.0148

Gnomad4 ASJ exome AF: 0.0227

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0137

Gnomad4 FIN exome AF: 0.00579

Gnomad4 NFE exome AF: 0.0286

Gnomad4 OTH exome AF: 0.0202

GnomAD4 genome AF: 0.0160 AC: 2437 AN: 152226 Hom.: 37 Cov.: 33 AF XY: 0.0150 AC XY: 1118 AN XY: 74432

Gnomad4 AFR AF: 0.00457

Gnomad4 AMR AF: 0.00903

Gnomad4 ASJ AF: 0.0233

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.0149

Gnomad4 FIN AF: 0.00539

Gnomad4 NFE AF: 0.0267

Gnomad4 OTH AF: 0.0204

Alfa AF: 0.0187 Hom.: 2

Bravo AF: 0.0160

Asia WGS AF: 0.00347 AC: 13 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 15, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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	-0.29
CADD	Benign	17
DANN	Benign	0.90

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs3135826; hg19: chr10-123238968;