10-121479212-GATTA-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_000141.5(FGFR2):c.*641_*644del variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.00455 in 233,300 control chromosomes in the GnomAD database, including 6 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0045 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (3 hom.)
• Consequence: FGFR2 NM_000141.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:9
• Conservation: PhyloP100: 5.68

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 -10 ACMG points.

• BP6: Variant 10-121479212-GATTA-G is Benign according to our data. Variant chr10-121479212-GATTA-G is described in ClinVar as [Likely_benign]. Clinvar id is 298986.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00448 (681/152132) while in subpopulation NFE AF= 0.00525 (357/68002). AF 95% confidence interval is 0.0048. There are 3 homozygotes in gnomad4. There are 352 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 681 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGFR2	NM_000141.5	c.*641_*644del		3_prime_UTR_variant	18/18	ENST00000358487.10
FGFR2	NM_022970.4	c.*641_*644del		3_prime_UTR_variant	18/18	ENST00000457416.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGFR2	ENST00000358487.10	c.*641_*644del		3_prime_UTR_variant	18/18	1	NM_000141.5	A2
FGFR2	ENST00000457416.7	c.*641_*644del		3_prime_UTR_variant	18/18	1	NM_022970.4	P4

Frequencies

GnomAD3 genomes AF: 0.00448 AC: 681 AN: 152016 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00222

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00721

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.00415

Gnomad FIN AF: 0.0128

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00525

Gnomad OTH AF: 0.00336

GnomAD4 exome AF: 0.00468 AC: 380 AN: 81168 Hom.: 3 AF XY: 0.00475 AC XY: 178 AN XY: 37492

Gnomad4 AFR exome AF: 0.00180

Gnomad4 AMR exome AF: 0.00519

Gnomad4 ASJ exome AF: 0.00685

Gnomad4 EAS exome AF: 0.000717

Gnomad4 SAS exome AF: 0.00565

Gnomad4 FIN exome AF: 0.0146

Gnomad4 NFE exome AF: 0.00547

Gnomad4 OTH exome AF: 0.00462

GnomAD4 genome AF: 0.00448 AC: 681 AN: 152132 Hom.: 3 Cov.: 32 AF XY: 0.00473 AC XY: 352 AN XY: 74380

Gnomad4 AFR AF: 0.00222

Gnomad4 AMR AF: 0.00223

Gnomad4 ASJ AF: 0.00721

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.00416

Gnomad4 FIN AF: 0.0128

Gnomad4 NFE AF: 0.00525

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00490 Hom.: 0

Bravo AF: 0.00373

Asia WGS AF: 0.00231 AC: 8 AN: 3470

ClinVar

Significance: Likely benign

Submissions summary: Benign:9

Revision: criteria provided, single submitter

Submissions by phenotype

Crouzon syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Pfeiffer syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Beare-Stevenson cutis gyrata syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Isolated coronal synostosis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Levy-Hollister syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Jackson-Weiss syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Craniosynostosis syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Acrocephalosyndactyly type I Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Saethre-Chotzen syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs548465887; hg19: chr10-123238726;