chr19-3590190-G-C

Variant names:

• chr19-3590190-G-C
• rs1172324481
• NM_133261.3:c.939G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM4

The NM_133261.3(GIPC3):​c.939G>C​(p.Ter313Tyrext*?) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GIPC3 NM_133261.3 stop_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.491
• Publications: 0 publications found

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]

GIPC3 Gene-Disease associations (from GenCC):

• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive nonsyndromic hearing loss 15

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_133261.3 Downstream stopcodon found after 352 codons.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GIPC3	NM_133261.3	c.939G>C	p.Ter313Tyrext*?	stop_lost	Exon 6 of 6	ENST00000644452.3	NP_573568.1
GIPC3	NM_001411144.1	c.952G>C	p.Val318Leu	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.939G>C	p.Ter313Tyrext*?	stop_lost	Exon 6 of 6		NM_133261.3	ENSP00000493901.2
GIPC3	ENST00000644946.1	c.952G>C	p.Val318Leu	missense_variant	Exon 6 of 6			ENSP00000495068.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 23, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Pathogenic. The p.X313Tyrex tX99 variant in GIPC3 has not been previously reported in individuals with heari ng loss. The variant was absent in large population databases, however this indi vidual is Arab and ethnically matched data is not available in these databases t o accurately assess the frequency of this variant in the Arab population. This v ariant is predicted to result in the loss of the native stop codon leading to a 99 amino acid C-terminus extension of the protein. However, the impact of this e xtension on the normal function of the protein is currently unknown. In summary, while there is some suspicion for a pathogenic role given the impact of the var iant, the clinical significance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	14
DANN	Benign	0.71
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.23	T
MetaRNN	Uncertain	0.51	D
PhyloP100		0.49
GERP RS		3.3
Mutation Taster		=30/170	disease causing

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

Other links and lift over

dbSNP: rs1172324481; hg19: chr19-3590188;