19-3585676-C-G

Variant names:

• chr19-3585676-C-G
• rs370730002
• NM_133261.3:c.79C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_133261.3(GIPC3):​c.79C>G​(p.Pro27Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000846 in 1,182,322 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 8.5e-7 (0 hom.)
• Consequence: GIPC3 NM_133261.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0900

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09776446).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GIPC3	NM_133261.3	c.79C>G	p.Pro27Ala	missense_variant	Exon 1 of 6	ENST00000644452.3	NP_573568.1
GIPC3	NM_001411144.1	c.79C>G	p.Pro27Ala	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.79C>G	p.Pro27Ala	missense_variant	Exon 1 of 6		NM_133261.3	ENSP00000493901.2
GIPC3	ENST00000644946.1	c.79C>G	p.Pro27Ala	missense_variant	Exon 1 of 6			ENSP00000495068.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000157 AC: 1 AN: 63754 Hom.: 0 AF XY: 0.0000265 AC XY: 1 AN XY: 37740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000741

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 8.46e-7 AC: 1 AN: 1182322 Hom.: 0 Cov.: 30 AF XY: 0.00000173 AC XY: 1 AN XY: 577520

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: 0.0000218

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

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	Benign	0.051
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	7.3
DANN	Benign	0.89
DEOGEN2	Benign	0.13	T;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.32	.;T;T
M_CAP	Pathogenic	0.34	D
MetaRNN	Benign	0.098	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;L;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.7	N;.;.
REVEL	Benign	0.17
Sift	Benign	0.26	T;.;.
Sift4G	Benign	0.14	T;.;.
Polyphen		0.0040	B;B;.
Vest4		0.11
MutPred		0.15		Loss of catalytic residue at P27 (P = 0.0039);Loss of catalytic residue at P27 (P = 0.0039);Loss of catalytic residue at P27 (P = 0.0039);
MVP		0.55
MPC		0.096
ClinPred		0.14	T
GERP RS		-2.8
Varity_R		0.043
gMVP		0.29

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: rs370730002; hg19: chr19-3585674;