4-37960565-G-C

Position:

• chr4-37960565-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006607.3(PTTG2):​c.131G>C​(p.Arg44Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.594 in 1,613,780 control chromosomes in the GnomAD database, including 290,836 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.63 (31437 hom., cov: 31)
  • Exomes 𝑓: 0.59 (259399 hom.)
• Consequence: PTTG2 NM_006607.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.237

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.6032E-7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.935 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTTG2	NM_006607.3	c.131G>C	p.Arg44Pro	missense_variant	1/1	ENST00000504686.2	NP_006598.2
TBC1D1	NM_001396959.1	c.418-53944G>C		intron_variant		ENST00000698857.1	NP_001383888.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTTG2	ENST00000504686.2	c.131G>C	p.Arg44Pro	missense_variant	1/1		NM_006607.3	ENSP00000424261	P1
TBC1D1	ENST00000698857.1	c.418-53944G>C		intron_variant			NM_001396959.1	ENSP00000513987	A2

Frequencies

GnomAD3 genomes AF: 0.635 AC: 96394 AN: 151906 Hom.: 31374 Cov.: 31

Gnomad AFR AF: 0.704

Gnomad AMI AF: 0.378

Gnomad AMR AF: 0.699

Gnomad ASJ AF: 0.618

Gnomad EAS AF: 0.957

Gnomad SAS AF: 0.676

Gnomad FIN AF: 0.592

Gnomad MID AF: 0.579

Gnomad NFE AF: 0.562

Gnomad OTH AF: 0.628

GnomAD3 exomes AF: 0.646 AC: 162039 AN: 250724 Hom.: 54201 AF XY: 0.637 AC XY: 86454 AN XY: 135768

Gnomad AFR exome AF: 0.715

Gnomad AMR exome AF: 0.764

Gnomad ASJ exome AF: 0.627

Gnomad EAS exome AF: 0.957

Gnomad SAS exome AF: 0.670

Gnomad FIN exome AF: 0.598

Gnomad NFE exome AF: 0.556

Gnomad OTH exome AF: 0.616

GnomAD4 exome AF: 0.590 AC: 861839 AN: 1461756 Hom.: 259399 Cov.: 61 AF XY: 0.591 AC XY: 429599 AN XY: 727194

Gnomad4 AFR exome AF: 0.701

Gnomad4 AMR exome AF: 0.752

Gnomad4 ASJ exome AF: 0.627

Gnomad4 EAS exome AF: 0.961

Gnomad4 SAS exome AF: 0.666

Gnomad4 FIN exome AF: 0.593

Gnomad4 NFE exome AF: 0.558

Gnomad4 OTH exome AF: 0.616

GnomAD4 genome AF: 0.635 AC: 96518 AN: 152024 Hom.: 31437 Cov.: 31 AF XY: 0.641 AC XY: 47624 AN XY: 74320

Gnomad4 AFR AF: 0.705

Gnomad4 AMR AF: 0.699

Gnomad4 ASJ AF: 0.618

Gnomad4 EAS AF: 0.957

Gnomad4 SAS AF: 0.675

Gnomad4 FIN AF: 0.592

Gnomad4 NFE AF: 0.562

Gnomad4 OTH AF: 0.632

Alfa AF: 0.574 Hom.: 14239

Bravo AF: 0.648

TwinsUK AF: 0.552 AC: 2047

ALSPAC AF: 0.554 AC: 2135

ESP6500AA AF: 0.704 AC: 3099

ESP6500EA AF: 0.565 AC: 4855

ExAC AF: 0.641 AC: 77768

Asia WGS AF: 0.822 AC: 2855 AN: 3478

EpiCase AF: 0.555

EpiControl AF: 0.558

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.47
DANN	Benign	0.41
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.00021	N
LIST_S2	Benign	0.12	T
MetaRNN	Benign	8.6e-7	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-2.3	N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.34	T
PROVEAN	Benign	5.1	N
REVEL	Benign	0.058
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.034
MPC		0.030
ClinPred		0.0012	T
GERP RS		-4.0
gMVP		0.046

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

Publications

LitVar

Other links and lift over

dbSNP: rs6811863; hg19: chr4-37962186; COSMIC: COSV54716570;