chr19-3585655-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBS1_Supporting

The NM_133261.3(GIPC3):c.58C>T(p.Pro20Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000572 in 1,223,338 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000060 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000057 ( 0 hom. )

Consequence

GIPC3
NM_133261.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.80

Publications

2 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)
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

GIPC3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.18022805).

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000596 (9/151060) while in subpopulation EAS AF = 0.00175 (9/5148). AF 95% confidence interval is 0.000911. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GIPC3	NM_133261.3	MANE Select	c.58C>T	p.Pro20Ser	missense	Exon 1 of 6	NP_573568.1	Q8TF64
	GIPC3	NM_001411144.1		c.58C>T	p.Pro20Ser	missense	Exon 1 of 6	NP_001398073.1	A0A2R8Y651

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GIPC3	ENST00000644452.3	MANE Select	c.58C>T	p.Pro20Ser	missense	Exon 1 of 6	ENSP00000493901.2	Q8TF64
GIPC3	ENST00000644946.1		c.58C>T	p.Pro20Ser	missense	Exon 1 of 6	ENSP00000495068.1	A0A2R8Y651
GIPC3	ENST00000854561.1		c.58C>T	p.Pro20Ser	missense	Exon 1 of 6	ENSP00000524620.1

Frequencies

GnomAD3 genomes

AF:

0.0000596

AC:

AN:

150952

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:

0.00174

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

3786

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000569

AC:

AN:

1072278

Hom.:

Cov.:

AF XY:

0.0000526

AC XY:

AN XY:

512938

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

21670

American (AMR)

AF:

0.00

AC:

AN:

7398

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

12654

East Asian (EAS)

AF:

0.00249

AC:

AN:

23662

South Asian (SAS)

AF:

0.00

AC:

AN:

21366

European-Finnish (FIN)

AF:

0.00

AC:

AN:

23500

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2806

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

917346

Other (OTH)

AF:

0.0000478

AC:

AN:

41876

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.640

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000596

AC:

AN:

151060

Hom.:

Cov.:

AF XY:

0.0000542

AC XY:

AN XY:

73808

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41436

American (AMR)

AF:

0.00

AC:

AN:

15164

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3458

East Asian (EAS)

AF:

0.00175

AC:

AN:

5148

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10132

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67612

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.531

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000340

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.069

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.094

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.35

M_CAP

Pathogenic

0.90

MetaRNN

Benign

0.18

MetaSVM

Benign

-0.74

MutationAssessor

Benign

1.6

PhyloP100

1.8

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.21

REVEL

Benign

0.13

Sift

Benign

0.25

Sift4G

Benign

0.28

Polyphen

0.0010

Vest4

0.24

MutPred

0.24

Loss of catalytic residue at P20 (P = 0.0016)

MVP

0.76

MPC

0.10

ClinPred

0.15

GERP RS

3.6

PromoterAI

-0.048

Neutral

(source)

Varity_R

0.047

gMVP

0.31

Mutation Taster

=88/12

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over