19-3585719-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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 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

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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-3585719-C-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.815

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GIPC3	NM_133261.3	c.122C>T	p.Thr41Met	missense_variant	Exon 1 of 6	ENST00000644452.3	NP_573568.1
GIPC3	NM_001411144.1	c.122C>T	p.Thr41Met	missense_variant	Exon 1 of 6		NP_001398073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GIPC3	ENST00000644452.3	c.122C>T	p.Thr41Met	missense_variant	Exon 1 of 6		NM_133261.3	ENSP00000493901.2
GIPC3	ENST00000644946.1	c.122C>T	p.Thr41Met	missense_variant	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

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000191

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;T;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	.;D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.81	D;D;D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Uncertain	2.6	M;M;.
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;D;.
Vest4		0.62
MutPred		0.35		Loss of sheet (P = 0.0037);Loss of sheet (P = 0.0037);Loss of sheet (P = 0.0037);
MVP		0.91
MPC		0.42
ClinPred		0.99	D
GERP RS		3.6
Varity_R		0.15
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-3585717;