Genetic Variant GIPC3:c.-15C>T (chr19-3585583-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_133261.3(GIPC3):c.-15C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000819 in 1,147,434 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000087 ( 0 hom. )

Consequence

GIPC3
NM_133261.3 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.32

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]

GIPC3 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.66).

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
GIPC3	NM_133261.3 link	c.-15C>T	5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 6	ENST00000644452.3	NP_573568.1	Q8TF64
GIPC3	NM_133261.3 link	c.-15C>T	5_prime_UTR_variant	Exon 1 of 6	ENST00000644452.3	NP_573568.1	Q8TF64
GIPC3	NM_001411144.1 link	c.-15C>T	5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 6		NP_001398073.1
GIPC3	NM_001411144.1 link	c.-15C>T	5_prime_UTR_variant	Exon 1 of 6		NP_001398073.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
GIPC3	ENST00000644452 link	c.-15C>T	5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 6	NM_133261.3	ENSP00000493901.2	Q8TF64
GIPC3	ENST00000644452 link	c.-15C>T	5_prime_UTR_variant	Exon 1 of 6	NM_133261.3	ENSP00000493901.2	Q8TF64
GIPC3	ENST00000644946.1 link	c.-15C>T	upstream_gene_variant			ENSP00000495068.1	A0A2R8Y651

Frequencies

GnomAD3 genomes

AF:

0.0000461

AC:

AN:

151846

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000884

Gnomad OTH

AF:

0.000479

GnomAD4 exome

AF:

0.0000874

AC:

AN:

995588

Hom.:

Cov.:

AF XY:

0.0000852

AC XY:

AN XY:

469446

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000617

Gnomad4 NFE exome

AF:

0.0000981

Gnomad4 OTH exome

AF:

0.0000267

GnomAD4 genome

AF:

0.0000461

AC:

AN:

151846

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74170

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000884

Gnomad4 OTH

AF:

0.000479

Bravo

AF:

0.0000491

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 30, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.-15C>T variant in GIPC3 has not been previously reported in individuals with h earing loss. Data from large population studies is insufficient to assess the f requency of the variant. This variant is located in the 5' UTR, but its effect on translation is unknown. In summary, the clinical significance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.66

CADD

Benign

8.4

DANN

Benign

0.97

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over