rs387907001

Variant names:

• chr19-3589892-G-A
• rs387907001
• NM_133261.3:c.767G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

The NM_133261.3(GIPC3):​c.767G>A​(p.Gly256Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,586 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G256S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GIPC3 NM_133261.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.49
• Publications: 10 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_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_133261.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-3589891-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3601139.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.898
• PP5: Variant 19-3589892-G-A is Pathogenic according to our data. Variant chr19-3589892-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 30756.Status of the report is no_assertion_criteria_provided, 0 stars.

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.767G>A	p.Gly256Asp	missense	Exon 5 of 6	NP_573568.1	Q8TF64
	GIPC3	NM_001411144.1		c.767G>A	p.Gly256Asp	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.767G>A	p.Gly256Asp	missense	Exon 5 of 6	ENSP00000493901.2	Q8TF64
	GIPC3	ENST00000644946.1		c.767G>A	p.Gly256Asp	missense	Exon 5 of 6	ENSP00000495068.1	A0A2R8Y651
	GIPC3	ENST00000854561.1		c.698G>A	p.Gly233Asp	missense	Exon 5 of 6	ENSP00000524620.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461586 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727068

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53126

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Autosomal recessive nonsyndromic hearing loss 15 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		7.5
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.96	D
Vest4		0.80
MutPred		0.53		Gain of solvent accessibility (P = 0.0648)
MVP		0.98
MPC		0.31
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.85
gMVP		0.94
Mutation Taster		=4/96	disease causing (ClinVar)

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: rs387907001; hg19: chr19-3589890;