rs80060313

chr19-3585729-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 2P and 15B. PM2 BP4_Moderate BP6_Very_Strong BP7 BS1

The NM_133261.3(GIPC3):c.132G>C(p.Ala44=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000312 in 1,531,040 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: GIPC3 NM_133261.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.645

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 -13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 19-3585729-G-C is Benign according to our data. Variant chr19-3585729-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 227377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.645 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0017 (258/152090) while in subpopulation AFR AF= 0.00602 (250/41536). AF 95% confidence interval is 0.00541. There are 1 homozygotes in gnomad4. There are 112 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GIPC3	NM_133261.3	c.132G>C	p.Ala44=	synonymous_variant	1/6	ENST00000644452.3
GIPC3	NM_001411144.1	c.132G>C	p.Ala44=	synonymous_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GIPC3	ENST00000644452.3	c.132G>C	p.Ala44=	synonymous_variant	1/6		NM_133261.3	P1
GIPC3	ENST00000644946.1	c.132G>C	p.Ala44=	synonymous_variant	1/6

Frequencies

GnomAD3 genomes AF: 0.00169 AC: 257 AN: 151980 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00601

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000959

GnomAD3 exomes AF: 0.000210 AC: 27 AN: 128644 Hom.: 0 AF XY: 0.000170 AC XY: 12 AN XY: 70394

Gnomad AFR exome AF: 0.00545

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: 0.00

Gnomad NFE exome AF: 0.0000428

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000159 AC: 219 AN: 1378950 Hom.: 0 Cov.: 31 AF XY: 0.000135 AC XY: 92 AN XY: 680308

Gnomad4 AFR exome AF: 0.00656

Gnomad4 AMR exome AF: 0.0000867

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: 0.00000187

Gnomad4 OTH exome AF: 0.000280

GnomAD4 genome AF: 0.00170 AC: 258 AN: 152090 Hom.: 1 Cov.: 31 AF XY: 0.00151 AC XY: 112 AN XY: 74350

Gnomad4 AFR AF: 0.00602

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000949

Alfa AF: 0.000543 Hom.: 0

Bravo AF: 0.00181

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 11, 2015	p.Ala44Ala in Exon 01 of GIPC3: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and it is not located within the splice consensus sequence. This variant has been identified in 3/31 8 African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.bro adinstitute.org; dbSNP rs80060313). -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 03, 2018	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Nov 18, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 25, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
Cadd	Benign	8.4
Dann	Benign	0.90

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: rs80060313; hg19: chr19-3585727;