rs764177808

Variant names:

• chr12-98533940-C-A
• rs764177808
• ENST00000266732.8:c.1683C>A

Your query was ambiguous. Multiple possible variants found:

• chr12-98533940-C-A
• chr12-98533940-C-G
• chr12-98533940-C-T

Variant summary

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

The NM_003276.2(TMPO):​c.1683C>A​(p.Cys561*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TMPO NM_003276.2 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0280
• Publications: 3 publications found

Genes affected

TMPO (HGNC:11875): (thymopoietin) Through alternative splicing, this gene encodes several distinct LEM domain containing protein isoforms. LEM domain proteins include inner nuclear membrane and intranuclear proteins, and are involved in a variety of cellular functions including gene expression, chromatin organization, and replication and cell cycle control. The encoded alpha isoform is broadly diffuse in the nucleus and contains a lamin binding domain, while the beta and gamma isoforms are localized to the nuclear membrane and contain an HDAC3 interaction domain. The distinct isoforms may compete with each other when acting to chaperone other proteins and regulate transcription. [provided by RefSeq, Aug 2019]

TMPO Gene-Disease associations (from GenCC):

• familial isolated dilated cardiomyopathy

  Inheritance: Unknown, AD Classification: SUPPORTIVE, NO_KNOWN Submitted by: ClinGen, Orphanet
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• dilated cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003276.2. 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
	TMPO	NM_001032283.3	MANE Select	c.565+2102C>A		intron	N/A	NP_001027454.1	P42167-1
	TMPO	NM_003276.2		c.1683C>A	p.Cys561*	stop_gained	Exon 4 of 4	NP_003267.1	P42166-1
	TMPO	NM_001307975.2		c.565+2102C>A		intron	N/A	NP_001294904.1	G5E972

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPO	ENST00000266732.8	TSL:1	c.1683C>A	p.Cys561*	stop_gained	Exon 4 of 4	ENSP00000266732.4	P42166-1
	TMPO	ENST00000556029.6	TSL:1 MANE Select	c.565+2102C>A		intron	N/A	ENSP00000450627.1	P42167-1
	TMPO	ENST00000393053.6	TSL:1	c.565+2102C>A		intron	N/A	ENSP00000376773.2	P42167-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Loeys-Dietz syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Benign	2.6
DANN	Uncertain	0.98
Eigen	Benign	0.087
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.56	D
PhyloP100		-0.028
Vest4		0.75
GERP RS		-0.84
Mutation Taster		=40/160	disease causing

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: rs764177808; hg19: chr12-98927718;