1-156344667-C-G

Variant names:

• chr1-156344667-C-G
• rs1389613459
• NM_001304817.2:c.122C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001304817.2(TSACC):​c.122C>G​(p.Pro41Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: TSACC NM_001304817.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.795
• Publications: 0 publications found

Genes affected

TSACC (HGNC:30636): (TSSK6 activating cochaperone) Enables chaperone binding activity. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

CCT3 (HGNC:1616): (chaperonin containing TCP1 subunit 3) The protein encoded by this gene is a molecular chaperone that is a member of the chaperonin containing TCP1 complex (CCT), also known as the TCP1 ring complex (TRiC). This complex consists of two identical stacked rings, each containing eight different proteins. Unfolded polypeptides enter the central cavity of the complex and are folded in an ATP-dependent manner. The complex folds various proteins, including actin and tubulin. Alternate transcriptional splice variants have been characterized for this gene. In addition, a pseudogene of this gene has been found on chromosome 8. [provided by RefSeq, Aug 2010]

CCT3 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• neurodevelopmental disorder with speech or visual impairment and brain hypomyelination

  Inheritance: AD Classification: MODERATE Submitted by: G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32930452).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001304817.2. 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
	TSACC	NM_001304817.2	MANE Select	c.122C>G	p.Pro41Arg	missense	Exon 3 of 4	NP_001291746.1	Q96A04
	TSACC	NM_001304826.2		c.176C>G	p.Pro59Arg	missense	Exon 3 of 4	NP_001291755.1
	TSACC	NM_001304818.2		c.122C>G	p.Pro41Arg	missense	Exon 3 of 4	NP_001291747.1	Q96A04

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSACC	ENST00000368254.6	TSL:1 MANE Select	c.122C>G	p.Pro41Arg	missense	Exon 3 of 4	ENSP00000357237.1	Q96A04
	TSACC	ENST00000368252.5	TSL:1	c.122C>G	p.Pro41Arg	missense	Exon 3 of 4	ENSP00000357235.1	Q96A04
	TSACC	ENST00000368253.6	TSL:1	c.122C>G	p.Pro41Arg	missense	Exon 3 of 4	ENSP00000357236.1	Q96A04

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251338 AF XY: 0.00000736

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: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461826 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727224

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111976

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152160 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74310

African (AFR) AF: 0.00 AC: 0 AN: 41428

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000847 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.057	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	L
PhyloP100		0.80
PrimateAI	Benign	0.33	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Benign	0.10
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.010	D
Polyphen		0.91	P
Vest4		0.49
MVP		0.31
MPC		0.23
ClinPred		0.89	D
GERP RS		2.1
Varity_R		0.23
gMVP		0.18
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs1389613459; hg19: chr1-156314458;