rs876657816

Variant names:

• chr19-3589917-G-C
• rs876657816
• NM_133261.3:c.787+5G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 5P and 2B. PM1 PM2 PP3 BP6_Moderate

The NM_001411144.1(GIPC3):​c.792G>C​(p.Lys264Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GIPC3 NM_001411144.1 missense
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.50
• 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), PanelApp Australia
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_001411144.1
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 19-3589917-G-C is Benign according to our data. Variant chr19-3589917-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 228699.Status of the report is criteria_provided_single_submitter, 1 stars.

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.787+5G>C		splice_region intron	N/A	NP_573568.1	Q8TF64
	GIPC3	NM_001411144.1		c.792G>C	p.Lys264Asn	missense	Exon 5 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.787+5G>C		splice_region intron	N/A	ENSP00000493901.2	Q8TF64
	GIPC3	ENST00000644946.1		c.792G>C	p.Lys264Asn	missense	Exon 5 of 6	ENSP00000495068.1	A0A2R8Y651
	GIPC3	ENST00000854561.1		c.718+5G>C		splice_region intron	N/A	ENSP00000524620.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	25
DANN	Benign	0.97
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.20	T
MetaRNN	Uncertain	0.70	D
PhyloP100		7.5
GERP RS		4.3
Mutation Taster		=31/69	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.54		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.54		Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs876657816; hg19: chr19-3589915;