chr4-37960924-C-A

Variant names:

• chr4-37960924-C-A
• rs982602890
• NM_006607.3:c.490C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006607.3(PTTG2):​c.490C>A​(p.Pro164Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,614,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PTTG2 NM_006607.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.948
• Publications: 0 publications found

Genes affected

PTTG2 (HGNC:9691): (pituitary tumor-transforming 2) Predicted to enable SH3 domain binding activity. Predicted to be involved in homologous chromosome segregation and negative regulation of mitotic sister chromatid separation. Predicted to be located in cytoplasm. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

TBC1D1 (HGNC:11578): (TBC1 domain family member 1) TBC1D1 is the founding member of a family of proteins sharing a 180- to 200-amino acid TBC domain presumed to have a role in regulating cell growth and differentiation. These proteins share significant homology with TRE2 (USP6; MIM 604334), yeast Bub2, and CDC16 (MIM 603461) (White et al., 2000 [PubMed 10965142]).[supplied by OMIM, Mar 2008]

TBC1D1 Gene-Disease associations (from GenCC):

• non-syndromic renal or urinary tract malformation

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• congenital anomaly of kidney and urinary tract

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21663225).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006607.3. 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
	PTTG2	NM_006607.3	MANE Select	c.490C>A	p.Pro164Thr	missense	Exon 1 of 1	NP_006598.2	Q9NZH5-2
	TBC1D1	NM_001396959.1	MANE Select	c.418-53585C>A		intron	N/A	NP_001383888.1	A0A8V8TNS9
	TBC1D1	NM_015173.4		c.418-53585C>A		intron	N/A	NP_055988.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTTG2	ENST00000504686.2	TSL:6 MANE Select	c.490C>A	p.Pro164Thr	missense	Exon 1 of 1	ENSP00000424261.1	Q9NZH5-2
	TBC1D1	ENST00000698857.1	MANE Select	c.418-53585C>A		intron	N/A	ENSP00000513987.1	A0A8V8TNS9
	TBC1D1	ENST00000261439.9	TSL:1	c.418-53585C>A		intron	N/A	ENSP00000261439.4	Q86TI0-1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152114 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461892 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727248

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112010

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

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152114 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74312

African (AFR) AF: 0.000169 AC: 7 AN: 41412

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000113

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	0.13
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	14
DANN	Uncertain	0.98
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.023	N
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.0010	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.95
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.099
Sift	Benign	0.10	T
Sift4G	Benign	0.37	T
Polyphen		1.0	D
Vest4		0.16
MVP		0.067
MPC		0.21
ClinPred		0.59	D
GERP RS		0.63
gMVP		0.47
Mutation Taster		=92/8	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: rs982602890; hg19: chr4-37962545;