rs2108389

Variant names:

• chr19-3591592-T-C
• rs2108389
• NM_133261.3:c.*1402T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001411144.1(GIPC3):​c.2354T>C​(p.Ile785Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.549 in 1,232,466 control chromosomes in the GnomAD database, including 191,709 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/9 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.61 (30077 hom., cov: 31)
  • Exomes 𝑓: 0.54 (161632 hom.)
• Consequence: GIPC3 NM_001411144.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.432
• Publications: 12 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012926161).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.84 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001411144.1. 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.*1402T>C		3_prime_UTR	Exon 6 of 6	NP_573568.1	Q8TF64
	GIPC3	NM_001411144.1		c.2354T>C	p.Ile785Thr	missense	Exon 6 of 6	NP_001398073.1	A0A2R8Y651

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GIPC3	ENST00000644452.3	MANE Select	c.*1402T>C		3_prime_UTR	Exon 6 of 6	ENSP00000493901.2	Q8TF64
	GIPC3	ENST00000644946.1		c.2354T>C	p.Ile785Thr	missense	Exon 6 of 6	ENSP00000495068.1	A0A2R8Y651
	GIPC3	ENST00000854561.1		c.*1402T>C		3_prime_UTR	Exon 6 of 6	ENSP00000524620.1

Frequencies

GnomAD3 genomes AF: 0.605 AC: 91802 AN: 151714 Hom.: 30033 Cov.: 31

Gnomad AFR AF: 0.847

Gnomad AMI AF: 0.320

Gnomad AMR AF: 0.499

Gnomad ASJ AF: 0.561

Gnomad EAS AF: 0.163

Gnomad SAS AF: 0.372

Gnomad FIN AF: 0.511

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.552

Gnomad OTH AF: 0.607

GnomAD4 exome AF: 0.541 AC: 584530 AN: 1080634 Hom.: 161632 Cov.: 58 AF XY: 0.540 AC XY: 275531 AN XY: 510360

African (AFR) AF: 0.865 AC: 19878 AN: 22984

American (AMR) AF: 0.448 AC: 3777 AN: 8428

Ashkenazi Jewish (ASJ) AF: 0.551 AC: 7936 AN: 14402

East Asian (EAS) AF: 0.174 AC: 4607 AN: 26540

South Asian (SAS) AF: 0.395 AC: 7735 AN: 19606

European-Finnish (FIN) AF: 0.515 AC: 10989 AN: 21350

Middle Eastern (MID) AF: 0.572 AC: 1668 AN: 2918

European-Non Finnish (NFE) AF: 0.548 AC: 504888 AN: 920692

Other (OTH) AF: 0.527 AC: 23052 AN: 43714

GnomAD4 genome AF: 0.605 AC: 91900 AN: 151832 Hom.: 30077 Cov.: 31 AF XY: 0.597 AC XY: 44285 AN XY: 74170

African (AFR) AF: 0.847 AC: 35124 AN: 41470

American (AMR) AF: 0.499 AC: 7597 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.561 AC: 1945 AN: 3466

East Asian (EAS) AF: 0.164 AC: 841 AN: 5140

South Asian (SAS) AF: 0.371 AC: 1780 AN: 4792

European-Finnish (FIN) AF: 0.511 AC: 5378 AN: 10524

Middle Eastern (MID) AF: 0.629 AC: 185 AN: 294

European-Non Finnish (NFE) AF: 0.552 AC: 37491 AN: 67912

Other (OTH) AF: 0.604 AC: 1269 AN: 2100

Alfa AF: 0.572 Hom.: 72548

Bravo AF: 0.611

TwinsUK AF: 0.542 AC: 2008

ALSPAC AF: 0.549 AC: 2116

Asia WGS AF: 0.353 AC: 1230 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.95
DANN	Benign	0.51
FATHMM_MKL	Benign	0.0094	N
LIST_S2	Benign	0.22	T
MetaRNN	Benign	0.0013	T
PhyloP100		-0.43
GERP RS		-1.4
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2108389; hg19: chr19-3591590; COSMIC: COSV59258898; COSMIC: COSV59258898;