chr19-3586686-C-G

Variant names:

• chr19-3586686-C-G
• rs764713230
• NM_133261.3:c.411+6C>G

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

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).

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.411+6C>G		splice_region intron	N/A	NP_573568.1	Q8TF64
	GIPC3	NM_001411144.1		c.411+6C>G		splice_region intron	N/A	NP_001398073.1	A0A2R8Y651

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GIPC3	ENST00000644452.3	MANE Select	c.411+6C>G		splice_region intron	N/A	ENSP00000493901.2	Q8TF64
	GIPC3	ENST00000644946.1		c.411+6C>G		splice_region intron	N/A	ENSP00000495068.1	A0A2R8Y651
	GIPC3	ENST00000854561.1		c.342+75C>G		intron	N/A	ENSP00000524620.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 68284 Hom.: 0 Cov.: 19

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: 0 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: 4 AN: 344438 Hom.: 0 Cov.: 0 AF XY: 0.0000205 AC XY: 4 AN XY: 194740

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

African (AFR) AF: 0.00 AC: 0 AN: 10170

American (AMR) AF: 0.00 AC: 0 AN: 31718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10710

East Asian (EAS) AF: 0.00 AC: 0 AN: 11534

South Asian (SAS) AF: 0.0000169 AC: 1 AN: 59244

European-Finnish (FIN) AF: 0.0000346 AC: 1 AN: 28918

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2700

European-Non Finnish (NFE) AF: 0.0000115 AC: 2 AN: 174542

Other (OTH) AF: 0.00 AC: 0 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.

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 68292 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 AN XY: 32262

African (AFR) AF: 0.00 AC: 0 AN: 17626

American (AMR) AF: 0.00 AC: 0 AN: 4808

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1934

East Asian (EAS) AF: 0.00 AC: 0 AN: 2662

South Asian (SAS) AF: 0.00 AC: 0 AN: 2224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2322

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 164

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 35226

Other (OTH) AF: 0.00 AC: 0 AN: 836

Alfa AF: 0.000169 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.19
DANN	Benign	0.33
PhyloP100		-0.97
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs764713230; hg19: chr19-3586684;