19-3585719-C-T

Variant names:

• chr19-3585719-C-T
• rs727503062
• NM_133261.3:c.122C>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The NM_133261.3(GIPC3):​c.122C>T​(p.Thr41Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000015 in 1,331,658 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T41K) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: GIPC3 NM_133261.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.38
• 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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-3585719-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 163502.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.815

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133261.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GIPC3	NM_133261.3	MANE Select	c.122C>T	p.Thr41Met	missense	Exon 1 of 6	NP_573568.1
	GIPC3	NM_001411144.1		c.122C>T	p.Thr41Met	missense	Exon 1 of 6	NP_001398073.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GIPC3	ENST00000644452.3	MANE Select	c.122C>T	p.Thr41Met	missense	Exon 1 of 6	ENSP00000493901.2
	GIPC3	ENST00000644946.1		c.122C>T	p.Thr41Met	missense	Exon 1 of 6	ENSP00000495068.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000150 AC: 2 AN: 1331658 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 656666

African (AFR) AF: 0.00 AC: 0 AN: 27492

American (AMR) AF: 0.00 AC: 0 AN: 30192

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23244

East Asian (EAS) AF: 0.00 AC: 0 AN: 29354

South Asian (SAS) AF: 0.00 AC: 0 AN: 72598

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44884

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4830

European-Non Finnish (NFE) AF: 0.00000191 AC: 2 AN: 1044544

Other (OTH) AF: 0.00 AC: 0 AN: 54520

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		5.4
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.65
Sift	Benign	0.037	D
Sift4G	Benign	0.091	T
Polyphen		1.0	D
Vest4		0.62
MutPred		0.35		Loss of sheet (P = 0.0037)
MVP		0.91
MPC		0.42
ClinPred		0.99	D
GERP RS		3.6
PromoterAI		-0.045	Neutral
Varity_R		0.15
gMVP		0.67
Mutation Taster		=50/50

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: rs727503062; hg19: chr19-3585717;