chr19-3585678-C-A

Variant names:

• chr19-3585678-C-A
• rs1167794149
• NM_133261.3:c.81C>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_133261.3(GIPC3):​c.81C>A​(p.Pro27Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000414 in 1,208,448 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P27P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: GIPC3 NM_133261.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.275
• 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: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP7: Synonymous conserved (PhyloP=-0.275 with no splicing effect.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GIPC3	NM_133261.3	MANE Select	c.81C>A	p.Pro27Pro	synonymous	Exon 1 of 6	NP_573568.1	Q8TF64
	GIPC3	NM_001411144.1		c.81C>A	p.Pro27Pro	synonymous	Exon 1 of 6	NP_001398073.1	A0A2R8Y651

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GIPC3	ENST00000644452.3	MANE Select	c.81C>A	p.Pro27Pro	synonymous	Exon 1 of 6	ENSP00000493901.2	Q8TF64
	GIPC3	ENST00000644946.1		c.81C>A	p.Pro27Pro	synonymous	Exon 1 of 6	ENSP00000495068.1	A0A2R8Y651
	GIPC3	ENST00000854561.1		c.81C>A	p.Pro27Pro	synonymous	Exon 1 of 6	ENSP00000524620.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000414 AC: 5 AN: 1208448 Hom.: 0 Cov.: 31 AF XY: 0.00000338 AC XY: 2 AN XY: 592034

African (AFR) AF: 0.00 AC: 0 AN: 24936

American (AMR) AF: 0.00 AC: 0 AN: 21198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19646

East Asian (EAS) AF: 0.00 AC: 0 AN: 25614

South Asian (SAS) AF: 0.00 AC: 0 AN: 52312

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33898

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3448

European-Non Finnish (NFE) AF: 0.00000510 AC: 5 AN: 979588

Other (OTH) AF: 0.00 AC: 0 AN: 47808

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	14
DANN	Benign	0.95
PhyloP100		-0.28
PromoterAI		-0.0034	Neutral

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: rs1167794149; hg19: chr19-3585676;