chr1-186312564-T-G

Variant names:

• chr1-186312564-T-G
• rs7756
• NM_003292.3:c.*1407A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003292.3(TPR):​c.*1407A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.64 in 787,338 control chromosomes in the GnomAD database, including 162,257 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.63 (30693 hom., cov: 32)
  • Exomes 𝑓: 0.64 (131564 hom.)
• Consequence: TPR NM_003292.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.405
• Publications: 8 publications found

Genes affected

TPR (HGNC:12017): (translocated promoter region, nuclear basket protein) This gene encodes a large coiled-coil protein that forms intranuclear filaments attached to the inner surface of nuclear pore complexes (NPCs). The protein directly interacts with several components of the NPC. It is required for the nuclear export of mRNAs and some proteins. Oncogenic fusions of the 5' end of this gene with several different kinase genes occur in some neoplasias. [provided by RefSeq, Jul 2008]

PRG4 (HGNC:9364): (proteoglycan 4) The protein encoded by this gene is a large proteoglycan that is synthesized by chondrocytes located at the surface of articular cartilage and by some synovial lining cells. This protein contains both chondroitin sulfate and keratan sulfate glycosaminoglycans. It functions as a boundary lubricant at the cartilage surface and contributes to the elastic absorption and energy dissipation of synovial fluid. Mutations in this gene result in camptodactyly-arthropathy-coxa vara-pericarditis syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

PRG4 Gene-Disease associations (from GenCC):

• camptodactyly-arthropathy-coxa vara-pericarditis syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Illumina, ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.648 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPR	NM_003292.3	c.*1407A>C		3_prime_UTR_variant	Exon 51 of 51	ENST00000367478.9	NP_003283.2
PRG4	NM_005807.6	c.3991+192T>G		intron_variant	Intron 11 of 12	ENST00000445192.7	NP_005798.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPR	ENST00000367478.9	c.*1407A>C		3_prime_UTR_variant	Exon 51 of 51	1	NM_003292.3	ENSP00000356448.3
PRG4	ENST00000445192.7	c.3991+192T>G		intron_variant	Intron 11 of 12	5	NM_005807.6	ENSP00000399679.3

Frequencies

GnomAD3 genomes AF: 0.635 AC: 96367 AN: 151854 Hom.: 30638 Cov.: 32

Gnomad AFR AF: 0.628

Gnomad AMI AF: 0.541

Gnomad AMR AF: 0.609

Gnomad ASJ AF: 0.559

Gnomad EAS AF: 0.647

Gnomad SAS AF: 0.545

Gnomad FIN AF: 0.657

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.653

Gnomad OTH AF: 0.602

GnomAD4 exome AF: 0.641 AC: 407486 AN: 635364 Hom.: 131564 Cov.: 8 AF XY: 0.637 AC XY: 208806 AN XY: 327770

African (AFR) AF: 0.631 AC: 9840 AN: 15586

American (AMR) AF: 0.594 AC: 11728 AN: 19730

Ashkenazi Jewish (ASJ) AF: 0.547 AC: 8239 AN: 15058

East Asian (EAS) AF: 0.670 AC: 21603 AN: 32222

South Asian (SAS) AF: 0.549 AC: 26964 AN: 49076

European-Finnish (FIN) AF: 0.651 AC: 20727 AN: 31834

Middle Eastern (MID) AF: 0.515 AC: 1220 AN: 2368

European-Non Finnish (NFE) AF: 0.656 AC: 287042 AN: 437308

Other (OTH) AF: 0.625 AC: 20123 AN: 32182

GnomAD4 genome AF: 0.635 AC: 96475 AN: 151974 Hom.: 30693 Cov.: 32 AF XY: 0.634 AC XY: 47076 AN XY: 74276

African (AFR) AF: 0.629 AC: 26052 AN: 41426

American (AMR) AF: 0.609 AC: 9310 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.559 AC: 1938 AN: 3466

East Asian (EAS) AF: 0.647 AC: 3338 AN: 5158

South Asian (SAS) AF: 0.544 AC: 2622 AN: 4820

European-Finnish (FIN) AF: 0.657 AC: 6940 AN: 10558

Middle Eastern (MID) AF: 0.507 AC: 148 AN: 292

European-Non Finnish (NFE) AF: 0.653 AC: 44361 AN: 67962

Other (OTH) AF: 0.605 AC: 1275 AN: 2106

Alfa AF: 0.641 Hom.: 86050

Bravo AF: 0.632

Asia WGS AF: 0.645 AC: 2240 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.87
DANN	Benign	0.47
PhyloP100		-0.41
Mutation Taster		=100/0	polymorphism (auto)

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: rs7756; hg19: chr1-186281696; COSMIC: COSV104422618;