10-121487523-C-T

Variant names:

• chr10-121487523-C-T
• rs2981461
• NM_000141.5:c.1987-99G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000141.5(FGFR2):​c.1987-99G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.557 in 991,590 control chromosomes in the GnomAD database, including 160,533 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (18780 hom., cov: 34)
  • Exomes 𝑓: 0.57 (141753 hom.)
• Consequence: FGFR2 NM_000141.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.449
• Publications: 9 publications found

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]

FGFR2 Gene-Disease associations (from GenCC):

• Apert syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, PanelApp Australia, G2P, Genomics England PanelApp
• Beare-Stevenson cutis gyrata syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Genomics England PanelApp
• Crouzon syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, ClinGen, PanelApp Australia, Genomics England PanelApp, G2P
• Jackson-Weiss syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P
• LADD syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• Pfeiffer syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, G2P
• Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, G2P
• bent bone dysplasia syndrome 1

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• familial scaphocephaly syndrome, McGillivray type

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• Saethre-Chotzen syndrome

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia, Genomics England PanelApp
• Antley-Bixler syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• LADD syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Pfeiffer syndrome type 1

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Pfeiffer syndrome type 2

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Pfeiffer syndrome type 3

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 10-121487523-C-T is Benign according to our data. Variant chr10-121487523-C-T is described in ClinVar as Benign. ClinVar VariationId is 1221003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.61 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.1987-99G>A		intron_variant	Intron 14 of 17	ENST00000358487.10	NP_000132.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000358487.10	c.1987-99G>A		intron_variant	Intron 14 of 17	1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000457416.7	c.1990-99G>A		intron_variant	Intron 14 of 17	1		ENSP00000410294.2
FGFR2	ENST00000369056.5	c.1990-99G>A		intron_variant	Intron 13 of 16	1		ENSP00000358052.1
FGFR2	ENST00000369058.7	c.1990-99G>A		intron_variant	Intron 14 of 16	1		ENSP00000358054.3
FGFR2	ENST00000613048.4	c.1720-99G>A		intron_variant	Intron 13 of 16	5		ENSP00000484154.1
FGFR2	ENST00000369061.8	c.1651-99G>A		intron_variant	Intron 11 of 14	1		ENSP00000358057.4
FGFR2	ENST00000369059.5	c.1645-99G>A		intron_variant	Intron 12 of 15	5		ENSP00000358055.1
FGFR2	ENST00000360144.7	c.1723-99G>A		intron_variant	Intron 13 of 16	2		ENSP00000353262.3
FGFR2	ENST00000478859.5	c.1303-99G>A		intron_variant	Intron 13 of 16	1		ENSP00000474011.1
FGFR2	ENST00000429361.5	c.763-99G>A		intron_variant	Intron 6 of 8	5		ENSP00000404219.1
FGFR2	ENST00000604236.5	n.*1034-99G>A		intron_variant	Intron 13 of 16	1		ENSP00000474109.1

Frequencies

GnomAD3 genomes AF: 0.466 AC: 70737 AN: 151918 Hom.: 18768 Cov.: 34

Gnomad AFR AF: 0.206

Gnomad AMI AF: 0.476

Gnomad AMR AF: 0.620

Gnomad ASJ AF: 0.616

Gnomad EAS AF: 0.301

Gnomad SAS AF: 0.623

Gnomad FIN AF: 0.491

Gnomad MID AF: 0.557

Gnomad NFE AF: 0.577

Gnomad OTH AF: 0.498

GnomAD4 exome AF: 0.574 AC: 481593 AN: 839556 Hom.: 141753 AF XY: 0.576 AC XY: 250950 AN XY: 435622

African (AFR) AF: 0.201 AC: 4039 AN: 20064

American (AMR) AF: 0.704 AC: 24052 AN: 34160

Ashkenazi Jewish (ASJ) AF: 0.598 AC: 12898 AN: 21576

East Asian (EAS) AF: 0.340 AC: 11280 AN: 33150

South Asian (SAS) AF: 0.630 AC: 42159 AN: 66880

European-Finnish (FIN) AF: 0.504 AC: 24218 AN: 48098

Middle Eastern (MID) AF: 0.522 AC: 1733 AN: 3322

European-Non Finnish (NFE) AF: 0.593 AC: 339746 AN: 573004

Other (OTH) AF: 0.546 AC: 21468 AN: 39302

GnomAD4 genome AF: 0.465 AC: 70766 AN: 152034 Hom.: 18780 Cov.: 34 AF XY: 0.467 AC XY: 34743 AN XY: 74334

African (AFR) AF: 0.206 AC: 8545 AN: 41510

American (AMR) AF: 0.621 AC: 9477 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.616 AC: 2137 AN: 3468

East Asian (EAS) AF: 0.302 AC: 1561 AN: 5162

South Asian (SAS) AF: 0.624 AC: 3011 AN: 4822

European-Finnish (FIN) AF: 0.491 AC: 5190 AN: 10566

Middle Eastern (MID) AF: 0.568 AC: 166 AN: 292

European-Non Finnish (NFE) AF: 0.577 AC: 39198 AN: 67928

Other (OTH) AF: 0.497 AC: 1048 AN: 2108

Alfa AF: 0.533 Hom.: 58336

Bravo AF: 0.464

Asia WGS AF: 0.476 AC: 1654 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.12
DANN	Benign	0.37
PhyloP100		-0.45
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2981461; hg19: chr10-123247037; COSMIC: COSV60660478; COSMIC: COSV60660478;