chr19-3585804-C-T

Variant names:

• chr19-3585804-C-T
• rs727504653
• NM_133261.3:c.207C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_133261.3(GIPC3):​c.207C>T​(p.Phe69Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000512 in 1,546,174 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00059 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00050 (9 hom.)
• Consequence: GIPC3 NM_133261.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.795
• 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)
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 19-3585804-C-T is Benign according to our data. Variant chr19-3585804-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 179131.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.795 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 9 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.207C>T	p.Phe69Phe	synonymous	Exon 1 of 6	NP_573568.1	Q8TF64
	GIPC3	NM_001411144.1		c.207C>T	p.Phe69Phe	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.207C>T	p.Phe69Phe	synonymous	Exon 1 of 6	ENSP00000493901.2	Q8TF64
	GIPC3	ENST00000644946.1		c.207C>T	p.Phe69Phe	synonymous	Exon 1 of 6	ENSP00000495068.1	A0A2R8Y651
	GIPC3	ENST00000854561.1		c.207C>T	p.Phe69Phe	synonymous	Exon 1 of 6	ENSP00000524620.1

Frequencies

GnomAD3 genomes AF: 0.000593 AC: 90 AN: 151818 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00119 AC: 168 AN: 141432 AF XY: 0.00111

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0172

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000441

Gnomad OTH exome AF: 0.000717

GnomAD4 exome AF: 0.000503 AC: 701 AN: 1394240 Hom.: 9 Cov.: 31 AF XY: 0.000496 AC XY: 341 AN XY: 687854

African (AFR) AF: 0.0000953 AC: 3 AN: 31488

American (AMR) AF: 0.0000561 AC: 2 AN: 35668

Ashkenazi Jewish (ASJ) AF: 0.0180 AC: 452 AN: 25120

East Asian (EAS) AF: 0.00 AC: 0 AN: 35536

South Asian (SAS) AF: 0.00 AC: 0 AN: 79164

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45424

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5620

European-Non Finnish (NFE) AF: 0.000152 AC: 164 AN: 1078306

Other (OTH) AF: 0.00138 AC: 80 AN: 57914

GnomAD4 genome AF: 0.000592 AC: 90 AN: 151934 Hom.: 1 Cov.: 31 AF XY: 0.000431 AC XY: 32 AN XY: 74268

African (AFR) AF: 0.0000483 AC: 2 AN: 41420

American (AMR) AF: 0.0000655 AC: 1 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.0199 AC: 69 AN: 3472

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

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

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 67932

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.00235 Hom.: 2

Bravo AF: 0.000620

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	GIPC3-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	13
DANN	Benign	0.97
PhyloP100		0.80
PromoterAI		-0.031	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: rs727504653; hg19: chr19-3585802;