rs727503062

chr19-3585719-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_133261.3(GIPC3):c.122C>A(p.Thr41Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000741 in 1,483,562 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: GIPC3 NM_133261.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 5.38

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.891
• PP5: Variant 19-3585719-C-A is Pathogenic according to our data. Variant chr19-3585719-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 163502.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1, Likely_pathogenic=2}. Variant chr19-3585719-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GIPC3	NM_133261.3	c.122C>A	p.Thr41Lys	missense_variant	1/6	ENST00000644452.3
GIPC3	NM_001411144.1	c.122C>A	p.Thr41Lys	missense_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GIPC3	ENST00000644452.3	c.122C>A	p.Thr41Lys	missense_variant	1/6		NM_133261.3	P1
GIPC3	ENST00000644946.1	c.122C>A	p.Thr41Lys	missense_variant	1/6

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151906 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000196 AC: 2 AN: 102036 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 56872

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000278

Gnomad OTH exome AF: 0.000351

GnomAD4 exome AF: 0.00000676 AC: 9 AN: 1331656 Hom.: 0 Cov.: 31 AF XY: 0.00000761 AC XY: 5 AN XY: 656664

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000275

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000479

Gnomad4 OTH exome AF: 0.0000367

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151906 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74180

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000870 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 21, 2023	For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GIPC3 protein function. ClinVar contains an entry for this variant (Variation ID: 163502). This missense change has been observed in individuals with nonsyndromic deafness (PMID: 23510777, 32747562, 32864763). It has also been observed to segregate with disease in related individuals. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 41 of the GIPC3 protein (p.Thr41Lys). -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 08, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 32864763, 23510777, 32747562) -

Rare genetic deafness Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 18, 2016

The p.Thr41Lys variant in GIPC3 has been previously identified in one consanguin eous Saudi Arabian family with prelingual severe to profound sensorineural heari ng loss and was not identified among 400 ethnically matched control chromosomes (Ramzan 2013). The Thr41Lys variant segregated in the homozygous state in five a ffected siblings, while the parents and two unaffected siblings were either hete rozygous for the variant or were wild-type (Ramzan 2013). However, the reported segregation data cannot rule out linkage disequilibrium between the Thr41Lys var iant and another causative variant. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pa thogenic based on the segregation data from the previously reported family. -

Sensorineural hearing loss disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Aug 04, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.68	D;D;.
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Uncertain	-0.048	T
MutationAssessor	Uncertain	2.6	M;M;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-3.5	D;.;.
REVEL	Pathogenic	0.77
Sift	Benign	0.059	T;.;.
Sift4G	Benign	0.086	T;.;.
Polyphen		0.65	P;P;.
Vest4		0.89
MVP		0.87
MPC		0.21
ClinPred		0.94	D
GERP RS		3.6
Varity_R		0.45
gMVP		0.79

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: rs727503062; hg19: chr19-3585717;