rs10426399

Variant names:

• chr19-3589437-C-T
• rs10426399
• NM_133261.3:c.593-6C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-3589437-C-T
• chr19-3589437-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_133261.3(GIPC3):​c.593-6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 1,608,168 control chromosomes in the GnomAD database, including 18,883 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (5207 hom., cov: 31)
  • Exomes 𝑓: 0.12 (13676 hom.)
• Consequence: GIPC3 NM_133261.3 splice_region, intron
• Scores: Splicing: ADA: 0.000009590
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.621
• Publications: 9 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 19-3589437-C-T is Benign according to our data. Variant chr19-3589437-C-T is described in ClinVar as Benign. ClinVar VariationId is 46572.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.46 is higher than 0.05.

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.593-6C>T		splice_region intron	N/A	NP_573568.1	Q8TF64
	GIPC3	NM_001411144.1		c.593-6C>T		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.593-6C>T		splice_region intron	N/A	ENSP00000493901.2	Q8TF64
	GIPC3	ENST00000644946.1		c.593-6C>T		splice_region intron	N/A	ENSP00000495068.1	A0A2R8Y651
	GIPC3	ENST00000854561.1		c.524-6C>T		splice_region intron	N/A	ENSP00000524620.1

Frequencies

GnomAD3 genomes AF: 0.207 AC: 31392 AN: 151810 Hom.: 5183 Cov.: 31

Gnomad AFR AF: 0.465

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.119

Gnomad ASJ AF: 0.114

Gnomad EAS AF: 0.0488

Gnomad SAS AF: 0.0968

Gnomad FIN AF: 0.0762

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.119

Gnomad OTH AF: 0.168

GnomAD2 exomes AF: 0.123 AC: 30853 AN: 251216 AF XY: 0.117

Gnomad AFR exome AF: 0.477

Gnomad AMR exome AF: 0.0715

Gnomad ASJ exome AF: 0.105

Gnomad EAS exome AF: 0.0469

Gnomad FIN exome AF: 0.0788

Gnomad NFE exome AF: 0.117

Gnomad OTH exome AF: 0.108

GnomAD4 exome AF: 0.122 AC: 177041 AN: 1456240 Hom.: 13676 Cov.: 31 AF XY: 0.120 AC XY: 86665 AN XY: 724818

African (AFR) AF: 0.485 AC: 16174 AN: 33368

American (AMR) AF: 0.0771 AC: 3448 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 2700 AN: 26106

East Asian (EAS) AF: 0.0483 AC: 1915 AN: 39670

South Asian (SAS) AF: 0.100 AC: 8650 AN: 86170

European-Finnish (FIN) AF: 0.0804 AC: 4290 AN: 53370

Middle Eastern (MID) AF: 0.130 AC: 749 AN: 5754

European-Non Finnish (NFE) AF: 0.118 AC: 130852 AN: 1106874

Other (OTH) AF: 0.137 AC: 8263 AN: 60214

GnomAD4 genome AF: 0.207 AC: 31464 AN: 151928 Hom.: 5207 Cov.: 31 AF XY: 0.201 AC XY: 14928 AN XY: 74292

African (AFR) AF: 0.466 AC: 19264 AN: 41344

American (AMR) AF: 0.118 AC: 1808 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 396 AN: 3472

East Asian (EAS) AF: 0.0487 AC: 252 AN: 5176

South Asian (SAS) AF: 0.0971 AC: 467 AN: 4808

European-Finnish (FIN) AF: 0.0762 AC: 807 AN: 10590

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.119 AC: 8055 AN: 67964

Other (OTH) AF: 0.166 AC: 348 AN: 2098

Alfa AF: 0.127 Hom.: 2640

Bravo AF: 0.222

Asia WGS AF: 0.102 AC: 356 AN: 3478

EpiCase AF: 0.117

EpiControl AF: 0.117

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.95
DANN	Benign	0.47
PhyloP100		-0.62
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000096
dbscSNV1_RF	Benign	0.0020
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

Other links and lift over

dbSNP: rs10426399; hg19: chr19-3589435; COSMIC: COSV59259169;