19-3585617-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM2 BP4_Moderate BP6 BS1

The NM_133261.3(GIPC3):c.20G>A(p.Arg7Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000067 in 1,164,310 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: GIPC3 NM_133261.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 0.661

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 Likely_benign. Variant got -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21502843).
• BP6: Variant 19-3585617-G-A is Benign according to our data. Variant chr19-3585617-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 517411.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=2}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000277 (42/151470) while in subpopulation AFR AF= 0.000869 (36/41442). AF 95% confidence interval is 0.000645. There are 0 homozygotes in gnomad4. There are 25 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GIPC3	NM_133261.3	c.20G>A	p.Arg7Gln	missense_variant	1/6	ENST00000644452.3
GIPC3	NM_001411144.1	c.20G>A	p.Arg7Gln	missense_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GIPC3	ENST00000644452.3	c.20G>A	p.Arg7Gln	missense_variant	1/6		NM_133261.3	P1
GIPC3	ENST00000644946.1	c.20G>A	p.Arg7Gln	missense_variant	1/6

Frequencies

GnomAD3 genomes AF: 0.000277 AC: 42 AN: 151362 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000871

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000395

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000355 AC: 36 AN: 1012840 Hom.: 0 Cov.: 30 AF XY: 0.0000292 AC XY: 14 AN XY: 479546

Gnomad4 AFR exome AF: 0.00128

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000210

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000341

Gnomad4 OTH exome AF: 0.0000781

GnomAD4 genome AF: 0.000277 AC: 42 AN: 151470 Hom.: 0 Cov.: 31 AF XY: 0.000338 AC XY: 25 AN XY: 74040

Gnomad4 AFR AF: 0.000869

Gnomad4 AMR AF: 0.000394

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000285 Hom.: 0

Bravo AF: 0.000404

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Apr 07, 2023	This variant is present in population databases (no rsID available, gnomAD 0.07%). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Not Available"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 517411). This variant has not been reported in the literature in individuals affected with GIPC3-related conditions. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 7 of the GIPC3 protein (p.Arg7Gln). -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 05, 2019	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 20, 2023

The c.20G>A (p.R7Q) alteration is located in exon 1 (coding exon 1) of the GIPC3 gene. This alteration results from a G to A substitution at nucleotide position 20, causing the arginine (R) at amino acid position 7 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 28, 2017

p.Arg7Gln of GIPC3: This variant is not expected to have clinical significance d ue to a lack of conservation across species, including mammals. Of note, 19 spec ies carry a glutamine (Gln) at this position, supporting that this change may be tolerated. In addition, computational prediction tools do not suggest a high li kelihood of impact to the protein. It has also been identified in 6/8510 African chromosomes by the genome Aggregation Database (gnomAD, http://gnomad.broadinst itute.org/; dbSNP rs998073430). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	17
Dann	Benign	0.93
DEOGEN2	Benign	0.080	T;T;.
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.39	N
M_CAP	Pathogenic	0.84	D
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.20	N;N;.
MutationTaster	Benign	0.99	N
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.71	N;.;.
REVEL	Benign	0.18
Sift	Benign	0.093	T;.;.
Sift4G	Benign	0.53	T;.;.
Polyphen		0.0050	B;B;.
Vest4		0.074
MutPred		0.17		Gain of loop (P = 0.0079);Gain of loop (P = 0.0079);Gain of loop (P = 0.0079);
MVP		0.81
MPC		0.12
ClinPred		0.11	T
GERP RS		0.12
Varity_R		0.042
gMVP		0.31

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: rs998073430; hg19: chr19-3585615;