NM_133261.3:c.69G>A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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 (★★). Synonymous variant affecting the same amino acid position (i.e. A23A) has been classified 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:8
• 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 -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 Benign/Likely_benign. ClinVar VariationId is 163501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 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>A	p.Ala23Ala	synonymous	Exon 1 of 6	NP_573568.1	Q8TF64
	GIPC3	NM_001411144.1		c.69G>A	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>A	p.Ala23Ala	synonymous	Exon 1 of 6	ENSP00000493901.2	Q8TF64
	GIPC3	ENST00000644946.1		c.69G>A	p.Ala23Ala	synonymous	Exon 1 of 6	ENSP00000495068.1	A0A2R8Y651
	GIPC3	ENST00000854561.1		c.69G>A	p.Ala23Ala	synonymous	Exon 1 of 6	ENSP00000524620.1

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

GnomAD2 exomes AF: 0.000773 AC: 16 AN: 20708 AF XY: 0.000743

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 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

African (AFR) AF: 0.0000903 AC: 2 AN: 22146

American (AMR) AF: 0.000468 AC: 4 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: 0.000148 AC: 4 AN: 27080

European-Finnish (FIN) AF: 0.000223 AC: 6 AN: 26912

Middle Eastern (MID) AF: 0.00101 AC: 3 AN: 2968

European-Non Finnish (NFE) AF: 0.00164 AC: 1533 AN: 934820

Other (OTH) AF: 0.00152 AC: 66 AN: 43330

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

African (AFR) AF: 0.000193 AC: 8 AN: 41414

American (AMR) AF: 0.000660 AC: 10 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: 0.000208 AC: 1 AN: 4818

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

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.00127 AC: 86 AN: 67632

Other (OTH) AF: 0.00144 AC: 3 AN: 2090

Alfa AF: 0.000160 Hom.: 0

Bravo AF: 0.000854

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	not specified (2)
-	-	1	Autosomal recessive nonsyndromic hearing loss 15 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	12
DANN	Benign	0.97
PhyloP100		-0.40
PromoterAI		-0.011	Neutral
Mutation Taster		=98/2	polymorphism

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;