19-3585601-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_133261.3(GIPC3):c.4G>A(p.Glu2Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,155,790 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 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 0.0011 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0011 (1 hom.)
• Consequence: GIPC3 NM_133261.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 2.07

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 -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03703049).
• BP6: Variant 19-3585601-G-A is Benign according to our data. Variant chr19-3585601-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 505606.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=3}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00105 (160/151826) while in subpopulation NFE AF= 0.00125 (85/67888). AF 95% confidence interval is 0.00104. There are 0 homozygotes in gnomad4. There are 92 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.4G>A	p.Glu2Lys	missense_variant	1/6	ENST00000644452.3
GIPC3	NM_001411144.1	c.4G>A	p.Glu2Lys	missense_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GIPC3	ENST00000644452.3	c.4G>A	p.Glu2Lys	missense_variant	1/6		NM_133261.3	P1
GIPC3	ENST00000644946.1	c.4G>A	p.Glu2Lys	missense_variant	1/6

Frequencies

GnomAD3 genomes AF: 0.00105 AC: 160 AN: 151720 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00538

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00125

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.00432 AC: 3 AN: 694 Hom.: 0 AF XY: 0.00476 AC XY: 2 AN XY: 420

Gnomad AFR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad FIN exome AF: 0.00455

Gnomad NFE exome AF: 0.00437

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00108 AC: 1087 AN: 1003964 Hom.: 1 Cov.: 30 AF XY: 0.00106 AC XY: 503 AN XY: 474734

Gnomad4 AFR exome AF: 0.0000499

Gnomad4 AMR exome AF: 0.000512

Gnomad4 ASJ exome AF: 0.00215

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00457

Gnomad4 NFE exome AF: 0.00106

Gnomad4 OTH exome AF: 0.00150

GnomAD4 genome AF: 0.00105 AC: 160 AN: 151826 Hom.: 0 Cov.: 31 AF XY: 0.00124 AC XY: 92 AN XY: 74250

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00538

Gnomad4 NFE AF: 0.00125

Gnomad4 OTH AF: 0.000475

Alfa AF: 0.00122 Hom.: 0

Bravo AF: 0.000623

ExAC AF: 0.000158 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 11, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 28, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 25, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2016	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 07, 2017

The p.Glu2Lys variant in GIPC3 has not been previously reported in individuals w ith hearing loss or in large population studies. Computational prediction tools and conservation analysis suggest that the p.Glu2Lys variant may not impact the protein, though this information is not predictive enough to rule out pathogenic ity. In summary, the clinical significance of the p.Glu2Lys variant is uncertain . -

GIPC3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 20, 2023

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	Uncertain	0.35
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.10	T;T;.
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.68	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Benign	0.037	T;T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.1	L;L;.
MutationTaster	Benign	0.56	D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.84	N;.;.
REVEL	Benign	0.25
Sift	Pathogenic	0.0	D;.;.
Sift4G	Benign	0.064	T;.;.
Polyphen		0.0	B;B;.
Vest4		0.19
MVP		0.72
MPC		0.11
ClinPred		0.27	T
GERP RS		2.5
Varity_R		0.26
gMVP		0.51

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: rs764467903; hg19: chr19-3585599;