rs727503064

Positions:

• chr19-3589524-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_133261.3(GIPC3):​c.674G>A​(p.Arg225His) variant causes a missense change. The variant allele was found at a frequency of 0.00000821 in 1,461,670 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R225C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: GIPC3 NM_133261.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.32

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GIPC3	NM_133261.3	c.674G>A	p.Arg225His	missense_variant	4/6	ENST00000644452.3
GIPC3	NM_001411144.1	c.674G>A	p.Arg225His	missense_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GIPC3	ENST00000644452.3	c.674G>A	p.Arg225His	missense_variant	4/6		NM_133261.3	P1
GIPC3	ENST00000644946.1	c.674G>A	p.Arg225His	missense_variant	4/6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000800 AC: 2 AN: 250068 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135600

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000997

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461670 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727128

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.000111 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 10, 2014

The p.Arg225His variant in GIPC3 has not been previously reported in individuals with hearing loss or in large population studies. Computational prediction tool s and conservation analysis suggest that this variant may impact the protein, th ough this information is not predictive enough to determine pathogenicity. In su mmary, the clinical significance of the p.Arg225His variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.62	D;D;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Pathogenic	0.50	D
MetaRNN	Uncertain	0.74	D;D;D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Uncertain	2.4	M;M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-4.6	D;.;.
REVEL	Uncertain	0.62
Sift	Benign	0.048	D;.;.
Sift4G	Uncertain	0.045	D;.;.
Polyphen		1.0	D;D;.
Vest4		0.81
MutPred		0.45		Loss of sheet (P = 0.0025);Loss of sheet (P = 0.0025);Loss of sheet (P = 0.0025);
MVP		0.94
MPC		0.54
ClinPred		0.99	D
GERP RS		3.4
Varity_R		0.30
gMVP		0.74

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

Publications

LitVar

Other links and lift over

dbSNP: rs727503064; hg19: chr19-3589522; COSMIC: COSV59259776; COSMIC: COSV59259776;