rs3135774

Variant names:

• chr10-121503964-C-G
• rs3135774
• NM_022970.4:c.1291-23G>C

Your query was ambiguous. Multiple possible variants found:

• chr10-121503964-C-G
• chr10-121503964-C-T

Variant summary

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

The NM_022970.4(FGFR2):​c.1291-23G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00843 in 1,613,614 control chromosomes in the GnomAD database, including 373 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (82 hom., cov: 32)
  • Exomes 𝑓: 0.0077 (291 hom.)
• Consequence: FGFR2 NM_022970.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.722
• Publications: 7 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=-0.74).
• BP6: Variant 10-121503964-C-G is Benign according to our data. Variant chr10-121503964-C-G is described in ClinVar as Benign. ClinVar VariationId is 675995.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0753 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022970.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFR2	NM_022970.4	MANE Plus Clinical	c.1291-23G>C		intron	N/A	NP_075259.4
	FGFR2	NM_000141.5	MANE Select	c.1288-23G>C		intron	N/A	NP_000132.3
	FGFR2	NM_001441087.1		c.1285-23G>C		intron	N/A	NP_001428016.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFR2	ENST00000457416.7	TSL:1 MANE Plus Clinical	c.1291-23G>C		intron	N/A	ENSP00000410294.2
	FGFR2	ENST00000358487.10	TSL:1 MANE Select	c.1288-23G>C		intron	N/A	ENSP00000351276.6
	FGFR2	ENST00000369056.5	TSL:1	c.1291-23G>C		intron	N/A	ENSP00000358052.1

Frequencies

GnomAD3 genomes AF: 0.0158 AC: 2397 AN: 152112 Hom.: 79 Cov.: 32

Gnomad AFR AF: 0.0178

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0783

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.0160

Gnomad SAS AF: 0.0139

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00313

Gnomad OTH AF: 0.0206

GnomAD2 exomes AF: 0.0207 AC: 5162 AN: 249812 AF XY: 0.0173

Gnomad AFR exome AF: 0.0181

Gnomad AMR exome AF: 0.103

Gnomad ASJ exome AF: 0.0165

Gnomad EAS exome AF: 0.0194

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00352

Gnomad OTH exome AF: 0.0203

GnomAD4 exome AF: 0.00765 AC: 11180 AN: 1461384 Hom.: 291 Cov.: 31 AF XY: 0.00743 AC XY: 5398 AN XY: 726970

African (AFR) AF: 0.0206 AC: 690 AN: 33468

American (AMR) AF: 0.0992 AC: 4432 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.0168 AC: 439 AN: 26126

East Asian (EAS) AF: 0.0183 AC: 728 AN: 39686

South Asian (SAS) AF: 0.0101 AC: 867 AN: 86166

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53342

Middle Eastern (MID) AF: 0.0238 AC: 137 AN: 5762

European-Non Finnish (NFE) AF: 0.00290 AC: 3228 AN: 1111802

Other (OTH) AF: 0.0109 AC: 657 AN: 60372

GnomAD4 genome AF: 0.0159 AC: 2418 AN: 152230 Hom.: 82 Cov.: 32 AF XY: 0.0173 AC XY: 1289 AN XY: 74418

African (AFR) AF: 0.0179 AC: 745 AN: 41534

American (AMR) AF: 0.0790 AC: 1208 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0156 AC: 54 AN: 3468

East Asian (EAS) AF: 0.0159 AC: 82 AN: 5170

South Asian (SAS) AF: 0.0143 AC: 69 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00313 AC: 213 AN: 68034

Other (OTH) AF: 0.0203 AC: 43 AN: 2114

Alfa AF: 0.00543 Hom.: 4

Bravo AF: 0.0221

Asia WGS AF: 0.0160 AC: 57 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	15
DANN	Benign	0.58
PhyloP100		0.72
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: rs3135774; hg19: chr10-123263478;