19-3590107-G-A
Variant names:
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_133261.3(GIPC3):c.856G>A(p.Val286Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00165 in 1,611,312 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0012 ( 1 hom., cov: 33)
Exomes 𝑓: 0.0017 ( 4 hom. )
Consequence
GIPC3
NM_133261.3 missense
NM_133261.3 missense
Scores
5
6
Clinical Significance
Conservation
PhyloP100: 1.82
Genes affected
GIPC3 (HGNC:18183): (GIPC PDZ domain containing family member 3) The protein encoded by this gene belongs to the GIPC family. Studies in mice suggest that this gene is required for postnatal maturation of the hair bundle and long-term survival of hair cells and spiral ganglion in the ear. Mutations in this gene are associated with autosomal recessive deafness. [provided by RefSeq, Dec 2011]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -13 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.026073903).
BP6
Variant 19-3590107-G-A is Benign according to our data. Variant chr19-3590107-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 163510.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2, Likely_benign=2}. Variant chr19-3590107-G-A is described in Lovd as [Likely_benign]. Variant chr19-3590107-G-A is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00119 (182/152346) while in subpopulation NFE AF= 0.00218 (148/68026). AF 95% confidence interval is 0.00189. There are 1 homozygotes in gnomad4. There are 81 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 4 AR gene
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| GIPC3 | ENST00000644452.3 | c.856G>A | p.Val286Ile | missense_variant | Exon 6 of 6 | NM_133261.3 | ENSP00000493901.2 | |||
| GIPC3 | ENST00000644946.1 | c.869G>A | p.Arg290His | missense_variant | Exon 6 of 6 | ENSP00000495068.1 |
Frequencies
GnomAD3 genomes 0.00120 AC: 182AN: 152228Hom.: 1 Cov.: 33
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GnomAD3 exomes AF: 0.00117 AC: 283AN: 242464Hom.: 0 AF XY: 0.00121 AC XY: 160AN XY: 131748
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GnomAD4 exome AF: 0.00170 AC: 2474AN: 1458966Hom.: 4 Cov.: 35 AF XY: 0.00169 AC XY: 1228AN XY: 725564
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GnomAD4 genome 0.00119 AC: 182AN: 152346Hom.: 1 Cov.: 33 AF XY: 0.00109 AC XY: 81AN XY: 74498
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:6
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:4
| Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 22, 2015 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 10, 2020 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 06, 2025 | - - |
| Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The GIPC3 p.Val286Ile variant was not identified in the literature but was identified in dbSNP (ID: rs138339125) and ClinVar (classified as uncertain significance by GeneDx and EGL Genetics, as likely benign by Invitae and as benign by Laboratory for Molecular Medicine). The variant was identified in control databases in 326 of 273846 chromosomes (1 homozygous) at a frequency of 0.00119 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 25 of 10050 chromosomes (freq: 0.002488), European (non-Finnish) in 243 of 124586 chromosomes (freq: 0.00195), European (Finnish) in 29 of 24102 chromosomes (freq: 0.001203), Other in 6 of 6970 chromosomes (freq: 0.000861), Latino in 21 of 34498 chromosomes (freq: 0.000609) and African in 2 of 24056 chromosomes (freq: 0.000083), but was not observed in the East Asian or South Asian populations. The p.Val286 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
| Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2025 | GIPC3: BS1, BS2 - |
not specified Benign:1
| Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 30, 2012 | Val286Ile in Exon 06 of GIPC3: This variant is not expected to have clinical sig nificance because it has been identified in 0.4% (26/7016) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs138339125). - |
GIPC3-related disorder Benign:1
| Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 28, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Uncertain
D
MetaRNN
Benign
T
ClinPred
T
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at