19-3590107-G-A

Variant names:

• chr19-3590107-G-A
• rs138339125
• NM_133261.3:c.856G>A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_133261.3(GIPC3):​c.856G>A​(p.Val286Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00165 in 1,611,312 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (4 hom.)
• Consequence: GIPC3 NM_133261.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 1.82

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.026073903).
• BP6: Variant 19-3590107-G-A is Benign according to our data. Variant chr19-3590107-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 163510.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2, Likely_benign=2}. Variant chr19-3590107-G-A is described in Lovd as [Likely_benign]. Variant chr19-3590107-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00119 (182/152346) while in subpopulation NFE AF= 0.00218 (148/68026). AF 95% confidence interval is 0.00189. There are 1 homozygotes in gnomad4. There are 81 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GIPC3	NM_133261.3	c.856G>A	p.Val286Ile	missense_variant	Exon 6 of 6	ENST00000644452.3	NP_573568.1
GIPC3	NM_001411144.1	c.869G>A	p.Arg290His	missense_variant	Exon 6 of 6		NP_001398073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GIPC3	ENST00000644452.3	c.856G>A	p.Val286Ile	missense_variant	Exon 6 of 6		NM_133261.3	ENSP00000493901.2
GIPC3	ENST00000644946.1	c.869G>A	p.Arg290His	missense_variant	Exon 6 of 6			ENSP00000495068.1

Frequencies

GnomAD3 genomes AF: 0.00120 AC: 182 AN: 152228 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00218

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00117 AC: 283 AN: 242464 Hom.: 0 AF XY: 0.00121 AC XY: 160 AN XY: 131748

Gnomad AFR exome AF: 0.0000651

Gnomad AMR exome AF: 0.000624

Gnomad ASJ exome AF: 0.00256

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00126

Gnomad NFE exome AF: 0.00187

Gnomad OTH exome AF: 0.00102

GnomAD4 exome AF: 0.00170 AC: 2474 AN: 1458966 Hom.: 4 Cov.: 35 AF XY: 0.00169 AC XY: 1228 AN XY: 725564

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000702

Gnomad4 ASJ exome AF: 0.00254

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000815

Gnomad4 FIN exome AF: 0.000851

Gnomad4 NFE exome AF: 0.00200

Gnomad4 OTH exome AF: 0.00141

GnomAD4 genome AF: 0.00119 AC: 182 AN: 152346 Hom.: 1 Cov.: 33 AF XY: 0.00109 AC XY: 81 AN XY: 74498

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000376

Gnomad4 NFE AF: 0.00218

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00201 Hom.: 0

Bravo AF: 0.00117

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00314 AC: 27

ExAC AF: 0.00109 AC: 132

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The GIPC3 p.Val286Ile variant was not identified in the literature but was identified in dbSNP (ID: rs138339125) and ClinVar (classified as uncertain significance by GeneDx and EGL Genetics, as likely benign by Invitae and as benign by Laboratory for Molecular Medicine). The variant was identified in control databases in 326 of 273846 chromosomes (1 homozygous) at a frequency of 0.00119 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 25 of 10050 chromosomes (freq: 0.002488), European (non-Finnish) in 243 of 124586 chromosomes (freq: 0.00195), European (Finnish) in 29 of 24102 chromosomes (freq: 0.001203), Other in 6 of 6970 chromosomes (freq: 0.000861), Latino in 21 of 34498 chromosomes (freq: 0.000609) and African in 2 of 24056 chromosomes (freq: 0.000083), but was not observed in the East Asian or South Asian populations. The p.Val286 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GIPC3: BS1, BS2 -

Jan 22, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 10, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Apr 30, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Val286Ile in Exon 06 of GIPC3: This variant is not expected to have clinical sig nificance because it has been identified in 0.4% (26/7016) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs138339125). -

GIPC3-related disorder Benign:1

Nov 28, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.30	T
M_CAP	Uncertain	0.088	D
MetaRNN	Benign	0.026	T
ClinPred		0.20	T
GERP RS		4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs138339125; hg19: chr19-3590105; COSMIC: COSV59259125; COSMIC: COSV59259125;