NM_133261.3:c.69G>C

Variant names:

• chr19-3585666-G-C
• rs150473323
• NM_133261.3:c.69G>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_133261.3(GIPC3):​c.69G>C​(p.Ala23Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000531 in 1,255,890 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A23A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0028 (4 hom., cov: 31)
  • Exomes 𝑓: 0.00022 (2 hom.)
• Consequence: GIPC3 NM_133261.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.400
• Publications: 2 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 19-3585666-G-C is Benign according to our data. Variant chr19-3585666-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 227381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.4 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00279 (421/151058) while in subpopulation AFR AF = 0.00992 (411/41414). AF 95% confidence interval is 0.00913. There are 4 homozygotes in GnomAd4. There are 192 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

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.69G>C	p.Ala23Ala	synonymous	Exon 1 of 6	NP_573568.1	Q8TF64
	GIPC3	NM_001411144.1		c.69G>C	p.Ala23Ala	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.69G>C	p.Ala23Ala	synonymous	Exon 1 of 6	ENSP00000493901.2	Q8TF64
	GIPC3	ENST00000644946.1		c.69G>C	p.Ala23Ala	synonymous	Exon 1 of 6	ENSP00000495068.1	A0A2R8Y651
	GIPC3	ENST00000854561.1		c.69G>C	p.Ala23Ala	synonymous	Exon 1 of 6	ENSP00000524620.1

Frequencies

GnomAD3 genomes AF: 0.00272 AC: 411 AN: 150950 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.00971

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000397

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: 0.0000296

Gnomad OTH AF: 0.000967

GnomAD2 exomes AF: 0.0000483 AC: 1 AN: 20708 AF XY: 0.00

Gnomad AFR exome AF: 0.00893

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000223 AC: 246 AN: 1104832 Hom.: 2 Cov.: 30 AF XY: 0.000190 AC XY: 101 AN XY: 532602

African (AFR) AF: 0.00966 AC: 214 AN: 22146

American (AMR) AF: 0.000702 AC: 6 AN: 8548

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14392

East Asian (EAS) AF: 0.00 AC: 0 AN: 24634

South Asian (SAS) AF: 0.00 AC: 0 AN: 27080

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26912

Middle Eastern (MID) AF: 0.000674 AC: 2 AN: 2968

European-Non Finnish (NFE) AF: 0.00000642 AC: 6 AN: 934822

Other (OTH) AF: 0.000415 AC: 18 AN: 43330

GnomAD4 genome AF: 0.00279 AC: 421 AN: 151058 Hom.: 4 Cov.: 31 AF XY: 0.00260 AC XY: 192 AN XY: 73794

African (AFR) AF: 0.00992 AC: 411 AN: 41414

American (AMR) AF: 0.000396 AC: 6 AN: 15148

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10144

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000296 AC: 2 AN: 67632

Other (OTH) AF: 0.000957 AC: 2 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00288

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	11
DANN	Benign	0.92
PhyloP100		-0.40
PromoterAI		0.0058	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: rs150473323; hg19: chr19-3585664;