dbSNP rs764713230: GIPC3:c.411+6C>G (chr19-3586686-C-G) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_133261.3(GIPC3):c.411+6C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 19)

Exomes 𝑓: 0.000012 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GIPC3
NM_133261.3 splice_region, intron

Scores

Splicing: ADA: 0.00001860

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.974

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GIPC3	NM_133261.3 link	c.411+6C>G		splice_region_variant, intron_variant	Intron 2 of 5	ENST00000644452.3	NP_573568.1
GIPC3	NM_001411144.1 link	c.411+6C>G		splice_region_variant, intron_variant	Intron 2 of 5		NP_001398073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GIPC3	ENST00000644452.3 link	c.411+6C>G		splice_region_variant, intron_variant	Intron 2 of 5		NM_133261.3	ENSP00000493901.2
GIPC3	ENST00000644946.1 link	c.411+6C>G		splice_region_variant, intron_variant	Intron 2 of 5			ENSP00000495068.1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

68284

Hom.:

Cov.:

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

241792

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000116

AC:

AN:

344438

Hom.:

Cov.:

AF XY:

0.0000205

AC XY:

AN XY:

194740

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

10170

American (AMR)

AF:

0.00

AC:

AN:

31718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

10710

East Asian (EAS)

AF:

0.00

AC:

AN:

11534

South Asian (SAS)

AF:

0.0000169

AC:

AN:

59244

European-Finnish (FIN)

AF:

0.0000346

AC:

AN:

28918

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2700

European-Non Finnish (NFE)

AF:

0.0000115

AC:

AN:

174542

Other (OTH)

AF:

0.00

AC:

AN:

14902

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

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

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

68292

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32262

African (AFR)

AF:

0.00

AC:

AN:

17626

American (AMR)

AF:

0.00

AC:

AN:

4808

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1934

East Asian (EAS)

AF:

0.00

AC:

AN:

2662

South Asian (SAS)

AF:

0.00

AC:

AN:

2224

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2322

Middle Eastern (MID)

AF:

0.00

AC:

AN:

164

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

35226

Other (OTH)

AF:

0.00

AC:

AN:

836

Alfa

AF:

0.000169

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.19

(source)

DANN

Benign

0.33

PhyloP100

-0.97

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000019

dbscSNV1_RF

Benign

0.014

SpliceAI score (max)

0.020

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over