19-3590190-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM4

The NM_133261.3(GIPC3):​c.939G>C​(p.Ter313Tyrext*?) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

GIPC3
NM_133261.3 stop_lost

Scores

1
2
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.491
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM4
Stoplost variant in NM_133261.3 Downstream stopcodon found after 352 codons.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GIPC3NM_133261.3 linkuse as main transcriptc.939G>C p.Ter313Tyrext*? stop_lost 6/6 ENST00000644452.3 NP_573568.1 Q8TF64
GIPC3NM_001411144.1 linkuse as main transcriptc.952G>C p.Val318Leu missense_variant 6/6 NP_001398073.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GIPC3ENST00000644452.3 linkuse as main transcriptc.939G>C p.Ter313Tyrext*? stop_lost 6/6 NM_133261.3 ENSP00000493901.2 Q8TF64
GIPC3ENST00000644946.1 linkuse as main transcriptc.952G>C p.Val318Leu missense_variant 6/6 ENSP00000495068.1 A0A2R8Y651

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
35
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJun 23, 2016Variant classified as Uncertain Significance - Favor Pathogenic. The p.X313Tyrex tX99 variant in GIPC3 has not been previously reported in individuals with heari ng loss. The variant was absent in large population databases, however this indi vidual is Arab and ethnically matched data is not available in these databases t o accurately assess the frequency of this variant in the Arab population. This v ariant is predicted to result in the loss of the native stop codon leading to a 99 amino acid C-terminus extension of the protein. However, the impact of this e xtension on the normal function of the protein is currently unknown. In summary, while there is some suspicion for a pathogenic role given the impact of the var iant, the clinical significance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.28
T
BayesDel_noAF
Benign
-0.64
CADD
Benign
14
DANN
Benign
0.71
Eigen
Pathogenic
0.69
Eigen_PC
Uncertain
0.45
FATHMM_MKL
Benign
0.74
D
LIST_S2
Benign
0.23
T
MetaRNN
Uncertain
0.51
D
GERP RS
3.3

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1172324481; hg19: chr19-3590188; API