rs199951984

chr19-3590122-G-Achr19-3590122-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2 BP4_Strong BP6_Very_Strong BS1

The NM_133261.3(GIPC3):c.871G>A(p.Ala291Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000153 in 1,611,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: GIPC3 NM_133261.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 6.24

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 -14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.024078935).
• BP6: Variant 19-3590122-G-A is Benign according to our data. Variant chr19-3590122-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 227384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000157 (229/1458758) while in subpopulation AMR AF= 0.00231 (102/44206). AF 95% confidence interval is 0.00194. There are 0 homozygotes in gnomad4_exome. There are 106 alleles in male gnomad4_exome subpopulation. Median coverage is 35. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GIPC3	NM_133261.3	c.871G>A	p.Ala291Thr	missense_variant	6/6	ENST00000644452.3
GIPC3	NM_001411144.1	c.884G>A	p.Arg295His	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GIPC3	ENST00000644452.3	c.871G>A	p.Ala291Thr	missense_variant	6/6		NM_133261.3	P1
GIPC3	ENST00000644946.1	c.884G>A	p.Arg295His	missense_variant	6/6

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000446 AC: 108 AN: 241992 Hom.: 0 AF XY: 0.000266 AC XY: 35 AN XY: 131504

Gnomad AFR exome AF: 0.0000658

Gnomad AMR exome AF: 0.00276

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000101

Gnomad OTH exome AF: 0.000170

GnomAD4 exome AF: 0.000157 AC: 229 AN: 1458758 Hom.: 0 Cov.: 35 AF XY: 0.000146 AC XY: 106 AN XY: 725416

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00231

Gnomad4 ASJ exome AF: 0.0000385

Gnomad4 EAS exome AF: 0.0000757

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.0000990

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152332 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74494

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000171 Hom.: 0

Bravo AF: 0.000204

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000462 AC: 56

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 10, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Feb 14, 2023	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 23, 2015

p.Ala291Thr in exon 6 of GIPC3: This variant is not expected to have clinical si gnificance because it has been identified in 0.6% (42/7424) of Latino chromosome s by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbS NP rs199951984). -

GIPC3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 01, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.13
Cadd	Pathogenic	31
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D;D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.024	T;T
MetaSVM	Uncertain	-0.037	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.7	D;.
REVEL	Uncertain	0.60
Sift	Uncertain	0.021	D;.
Sift4G	Uncertain	0.027	D;.
Polyphen		0.99	D;D
Vest4		0.43
MVP		0.92
MPC		0.42
ClinPred		0.16	T
GERP RS		4.3
Varity_R		0.24
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs199951984; hg19: chr19-3590120;