19-3585654-G-T

Variant names:

• chr19-3585654-G-T
• rs754337950
• NM_133261.3:c.57G>T

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.57G>T​(p.Ala19Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000164 in 1,219,268 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00017 (2 hom.)
• Consequence: GIPC3 NM_133261.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.326
• 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 19-3585654-G-T is Benign according to our data. Variant chr19-3585654-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 262317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.326 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000133 (20/150920) while in subpopulation SAS AF = 0.00145 (7/4812). AF 95% confidence interval is 0.000683. There are 0 homozygotes in GnomAd4. There are 12 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GIPC3	NM_133261.3	MANE Select	c.57G>T	p.Ala19Ala	synonymous	Exon 1 of 6	NP_573568.1
	GIPC3	NM_001411144.1		c.57G>T	p.Ala19Ala	synonymous	Exon 1 of 6	NP_001398073.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GIPC3	ENST00000644452.3	MANE Select	c.57G>T	p.Ala19Ala	synonymous	Exon 1 of 6	ENSP00000493901.2
	GIPC3	ENST00000644946.1		c.57G>T	p.Ala19Ala	synonymous	Exon 1 of 6	ENSP00000495068.1

Frequencies

GnomAD3 genomes AF: 0.000139 AC: 21 AN: 150812 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000133

Gnomad OTH AF: 0.000484

GnomAD2 exomes AF: 0.000593 AC: 2 AN: 3372 AF XY: 0.000988

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ 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: 0.000168 AC: 180 AN: 1068348 Hom.: 2 Cov.: 30 AF XY: 0.000212 AC XY: 108 AN XY: 510478

African (AFR) AF: 0.00 AC: 0 AN: 21584

American (AMR) AF: 0.000137 AC: 1 AN: 7312

Ashkenazi Jewish (ASJ) AF: 0.000239 AC: 3 AN: 12560

East Asian (EAS) AF: 0.0000425 AC: 1 AN: 23518

South Asian (SAS) AF: 0.00328 AC: 68 AN: 20756

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23210

Middle Eastern (MID) AF: 0.00287 AC: 8 AN: 2790

European-Non Finnish (NFE) AF: 0.0000885 AC: 81 AN: 914944

Other (OTH) AF: 0.000432 AC: 18 AN: 41674

GnomAD4 genome AF: 0.000133 AC: 20 AN: 150920 Hom.: 0 Cov.: 31 AF XY: 0.000163 AC XY: 12 AN XY: 73730

African (AFR) AF: 0.00 AC: 0 AN: 41398

American (AMR) AF: 0.000132 AC: 2 AN: 15146

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10114

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

European-Non Finnish (NFE) AF: 0.000133 AC: 9 AN: 67566

Other (OTH) AF: 0.000479 AC: 1 AN: 2088

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000113

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	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	-0.65
CADD	Benign	8.9
DANN	Benign	0.91
PhyloP100		-0.33
PromoterAI		-0.030	Neutral
Mutation Taster		=100/0	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: rs754337950; hg19: chr19-3585652;