rs121917705

Variant names:

• chr11-69818738-C-A
• rs121917705
• NM_005247.4:c.196G>T

Your query was ambiguous. Multiple possible variants found:

• chr11-69818738-C-A
• chr11-69818738-C-G
• chr11-69818738-C-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_005247.4(FGF3):​c.196G>T​(p.Gly66Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000745 in 1,341,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: FGF3 NM_005247.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 4.25
• Publications: 8 publications found

Genes affected

FGF3 (HGNC:3681): (fibroblast growth factor 3) The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell survival activities and are involved in a variety of biological processes including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion. This gene was identified by its similarity with mouse fgf3/int-2, a proto-oncogene activated in virally induced mammary tumors in the mouse. Frequent amplification of this gene has been found in human tumors, which may be important for neoplastic transformation and tumor progression. Studies of the similar genes in mouse and chicken suggested the role in inner ear formation. [provided by RefSeq, Jul 2008]

FGF3 Gene-Disease associations (from GenCC):

• deafness with labyrinthine aplasia, microtia, and microdontia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)

LOC107984368 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a chain Fibroblast growth factor 3 (size 221) in uniprot entity FGF3_HUMAN there are 10 pathogenic changes around while only 3 benign (77%) in NM_005247.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 11-69818738-C-A is Pathogenic according to our data. Variant chr11-69818738-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 13840.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGF3	NM_005247.4	c.196G>T	p.Gly66Cys	missense_variant	Exon 1 of 3	ENST00000334134.4	NP_005238.1
LOC107984368	XR_001748071.2	n.31C>A		non_coding_transcript_exon_variant	Exon 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGF3	ENST00000334134.4	c.196G>T	p.Gly66Cys	missense_variant	Exon 1 of 3	1	NM_005247.4	ENSP00000334122.2
ENSG00000300527	ENST00000772585.1	n.-233C>A		upstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.45e-7 AC: 1 AN: 1341960 Hom.: 0 Cov.: 32 AF XY: 0.00000151 AC XY: 1 AN XY: 662230

African (AFR) AF: 0.00 AC: 0 AN: 27310

American (AMR) AF: 0.00 AC: 0 AN: 30694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23702

East Asian (EAS) AF: 0.00 AC: 0 AN: 30622

South Asian (SAS) AF: 0.00 AC: 0 AN: 75086

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33940

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4388

European-Non Finnish (NFE) AF: 9.43e-7 AC: 1 AN: 1060476

Other (OTH) AF: 0.00 AC: 0 AN: 55742

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000896 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Deafness with labyrinthine aplasia, microtia, and microdontia Pathogenic:2 Other:1

Apr 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jan 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		4.3
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-6.6	D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.98		Loss of disorder (P = 0.0055);
MVP		0.89
MPC		1.0
ClinPred		1.0	D
GERP RS		2.6
Varity_R		0.75
gMVP		0.88
Mutation Taster		=10/90	disease causing (ClinVar)

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: rs121917705; hg19: chr11-69633506;