11-69816334-G-A
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_005247.4(FGF3):c.310C>T(p.Arg104*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,613,542 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
Consequence
NM_005247.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FGF3 | NM_005247.4 | c.310C>T | p.Arg104* | stop_gained | Exon 2 of 3 | ENST00000334134.4 | NP_005238.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152162Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251480Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135918
GnomAD4 exome AF: 0.0000144 AC: 21AN: 1461262Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14AN XY: 727008
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152280Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74456
ClinVar
Submissions by phenotype
Deafness with labyrinthine aplasia, microtia, and microdontia Pathogenic:3Other:1
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Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with deafness, congenital with inner ear agenesis, microtia, and microdontia (MIM#610706). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0204 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with at least 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (6 heterozygotes, 0 homozygotes). (SP) 0701 - Other downstream truncating variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic and pathogenic by clinical laboratories in ClinVar. Additionally, it has been observed as homozygous and compound heterozygous in several families with congenital deafness with inner ear agenesis, microtia, and microdontia (PMIDs: 17236138, 21480479, 21306635). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
not provided Pathogenic:1
Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 136 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 21480479, 22993869, 21306635, 17236138) -
FGF3-related disorder Pathogenic:1
The FGF3 c.310C>T variant is predicted to result in premature protein termination (p.Arg104*). This variant has been reported to be causative for autosomal recessive syndromic deafness with LAMM (labyrinthine aplasia, microtia, and microdontia) (Tekin et al. 2007. PubMed ID: 17236138; Riazuddin et al. 2011. PubMed ID: 21306635; Sensi et al. 2011. PubMed ID: 21480479). This variant is reported in 0.0065% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-69631102-G-A). Nonsense variants in FGF3 are expected to be pathogenic. This variant is interpreted as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at