Genetic Variant NM_133261.3:c.20G>T (chr19-3585617-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_133261.3(GIPC3):c.20G>T(p.Arg7Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000987 in 1,012,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R7Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 9.9e-7 ( 0 hom. )

Consequence

GIPC3
NM_133261.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.661

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

nonsyndromic genetic hearing loss
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
autosomal recessive nonsyndromic hearing loss 15
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

GIPC3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.29533044).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133261.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GIPC3	NM_133261.3	MANE Select	c.20G>T	p.Arg7Leu	missense	Exon 1 of 6	NP_573568.1
	GIPC3	NM_001411144.1		c.20G>T	p.Arg7Leu	missense	Exon 1 of 6	NP_001398073.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GIPC3	ENST00000644452.3	MANE Select	c.20G>T	p.Arg7Leu	missense	Exon 1 of 6	ENSP00000493901.2
	GIPC3	ENST00000644946.1		c.20G>T	p.Arg7Leu	missense	Exon 1 of 6	ENSP00000495068.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.87e-7

AC:

AN:

1012838

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

479544

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

20276

American (AMR)

AF:

0.00

AC:

AN:

6084

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

10978

East Asian (EAS)

AF:

0.00

AC:

AN:

19140

South Asian (SAS)

AF:

0.00

AC:

AN:

19010

European-Finnish (FIN)

AF:

0.0000561

AC:

AN:

17816

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2510

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

878598

Other (OTH)

AF:

0.00

AC:

AN:

38426

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.14

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.42

M_CAP

Pathogenic

0.92

MetaRNN

Benign

0.30

MetaSVM

Benign

-0.76

MutationAssessor

Benign

0.55

PhyloP100

0.66

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-1.2

REVEL

Benign

0.21

Sift

Benign

0.041

Sift4G

Uncertain

0.044

Polyphen

0.0010

Vest4

0.17

MutPred

0.24

Loss of MoRF binding (P = 0.0196)

MVP

0.81

MPC

0.12

ClinPred

0.18

GERP RS

0.12

PromoterAI

-0.0098

Neutral

(source)

Varity_R

0.082

gMVP

0.40

Mutation Taster

=85/15

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over