rs374129877

Positions:

• chr19-3589476-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_133261.3(GIPC3):​c.626G>A​(p.Cys209Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000103 in 1,613,926 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (1 hom.)
• Consequence: GIPC3 NM_133261.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.04

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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.064921856).
• BP6: Variant 19-3589476-G-A is Benign according to our data. Variant chr19-3589476-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 163508.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-3589476-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GIPC3	NM_133261.3	c.626G>A	p.Cys209Tyr	missense_variant	4/6	ENST00000644452.3	NP_573568.1
GIPC3	NM_001411144.1	c.626G>A	p.Cys209Tyr	missense_variant	4/6		NP_001398073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GIPC3	ENST00000644452.3	c.626G>A	p.Cys209Tyr	missense_variant	4/6		NM_133261.3	ENSP00000493901.2
GIPC3	ENST00000644946.1	c.626G>A	p.Cys209Tyr	missense_variant	4/6			ENSP00000495068.1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152094 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.000191

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000756 AC: 19 AN: 251314 Hom.: 0 AF XY: 0.0000883 AC XY: 12 AN XY: 135886

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 0.000150

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000102 AC: 149 AN: 1461832 Hom.: 1 Cov.: 32 AF XY: 0.000111 AC XY: 81 AN XY: 727220

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000120

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152094 Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7 AN XY: 74300

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000184 Hom.: 0

Bravo AF: 0.000204

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000988 AC: 12

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 22, 2014

Cys209Tyr in exon 4 of GIPC3: This variant is not expected to have clinical sign ificance due to a lack of conservation across species, including mammals. Of no te, at least 5 mammals have a tyrosine (Tyr) at this position despite high nearb y amino acid conservation. While this variant has previously been reported in on e individual with hearing loss, this individual was found to have a homozygous f rameshift variant in the USH1C gene which was a likely explanation of the hearin g loss (Shearer 2013). In addition, this variant has also been identified in 1/8 600 of European American chromosomes by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS/; dbSNP rs374129877). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	8.1
DANN	Benign	0.45
DEOGEN2	Benign	0.17	T;T;.
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.53	.;T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.065	T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.8	L;L;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.2	N;.;.
REVEL	Benign	0.19
Sift	Benign	1.0	T;.;.
Sift4G	Benign	0.93	T;.;.
Polyphen		0.0	B;B;.
Vest4		0.28
MVP		0.51
MPC		0.35
ClinPred		0.060	T
GERP RS		2.3
Varity_R		0.11
gMVP		0.67

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: rs374129877; hg19: chr19-3589474;