rs727504798

Variant names:

• chr12-98537585-T-G
• rs727504798
• ENST00000261210.9:c.676T>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The ENST00000261210.9(TMPO):​c.676T>G​(p.Leu226Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMPO ENST00000261210.9 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.304
• Publications: 0 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: AD Classification: SUPPORTIVE, NO_KNOWN Submitted by: ClinGen, Orphanet
• dilated cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.050140917).
• BP6: Variant 12-98537585-T-G is Benign according to our data. Variant chr12-98537585-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 179335.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPO	NM_001032283.3	c.663+13T>G		intron_variant	Intron 4 of 8	ENST00000556029.6	NP_001027454.1
TMPO	NM_001307975.2	c.663+13T>G		intron_variant	Intron 4 of 7		NP_001294904.1
TMPO	NM_001032284.3	c.663+13T>G		intron_variant	Intron 4 of 5		NP_001027455.1
TMPO	XM_005269132.5	c.663+13T>G		intron_variant	Intron 4 of 6		XP_005269189.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPO	ENST00000556029.6	c.663+13T>G		intron_variant	Intron 4 of 8	1	NM_001032283.3	ENSP00000450627.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Nov 01, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

633+13T>G in intron 4 of TMPO: This variant is not expected to have clinical sig nificance because it is not located within the splice consensus sequence. 633+1 3T>G in intron 4 of TMPO (allele frequency = n/a) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	12
DANN	Benign	0.23
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.29	T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.050	T
MetaSVM	Benign	-0.99	T
PhyloP100		0.30
PROVEAN	Benign	0.20	N
REVEL	Benign	0.086
Sift	Benign	0.13	T
Sift4G	Benign	0.36	T
Vest4		0.16
MutPred		0.21		Gain of sheet (P = 0.1451);
MVP		0.20
ClinPred		0.044	T
GERP RS		-0.13
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs727504798; hg19: chr12-98931363;