rs150473323

Positions:

• chr19-3585666-G-A
• chr19-3585666-G-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_133261.3(GIPC3):​c.69G>A​(p.Ala23Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00138 in 1,255,888 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00073 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0015 (3 hom.)
• Consequence: GIPC3 NM_133261.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.400

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 Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 19-3585666-G-A is Benign according to our data. Variant chr19-3585666-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 163501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-3585666-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000728 (110/151058) while in subpopulation NFE AF= 0.00127 (86/67632). AF 95% confidence interval is 0.00105. There are 1 homozygotes in gnomad4. There are 44 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GIPC3	NM_133261.3	c.69G>A	p.Ala23Ala	synonymous_variant	1/6	ENST00000644452.3	NP_573568.1
GIPC3	NM_001411144.1	c.69G>A	p.Ala23Ala	synonymous_variant	1/6		NP_001398073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GIPC3	ENST00000644452.3	c.69G>A	p.Ala23Ala	synonymous_variant	1/6		NM_133261.3	ENSP00000493901.2
GIPC3	ENST00000644946.1	c.69G>A	p.Ala23Ala	synonymous_variant	1/6			ENSP00000495068.1

Frequencies

GnomAD3 genomes AF: 0.000735 AC: 111 AN: 150950 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000194

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000661

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.00127

Gnomad OTH AF: 0.00145

GnomAD3 exomes AF: 0.000773 AC: 16 AN: 20708 Hom.: 0 AF XY: 0.000743 AC XY: 10 AN XY: 13450

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: 0.00

Gnomad FIN exome AF: 0.000252

Gnomad NFE exome AF: 0.00160

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00146 AC: 1618 AN: 1104830 Hom.: 3 Cov.: 30 AF XY: 0.00143 AC XY: 759 AN XY: 532602

Gnomad4 AFR exome AF: 0.0000903

Gnomad4 AMR exome AF: 0.000468

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000148

Gnomad4 FIN exome AF: 0.000223

Gnomad4 NFE exome AF: 0.00164

Gnomad4 OTH exome AF: 0.00152

GnomAD4 genome AF: 0.000728 AC: 110 AN: 151058 Hom.: 1 Cov.: 31 AF XY: 0.000596 AC XY: 44 AN XY: 73794

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000660

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00127

Gnomad4 OTH AF: 0.00144

Alfa AF: 0.000160 Hom.: 0

Bravo AF: 0.000854

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 18, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 26, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 02, 2021	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 20, 2017	p.Ala23Ala in exon 1 of GIPC3: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 0.1% (34/24076) Eur opean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broa dinstitute.org; dbSNP rs150473323) -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Autosomal recessive nonsyndromic hearing loss 15 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

May 23, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	12
DANN	Benign	0.97

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: rs150473323; hg19: chr19-3585664;