rs727504622

Variant names:

• chr12-98547667-C-T
• rs727504622
• NM_001032283.3:c.1174C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001032283.3(TMPO):​c.1174C>T​(p.Pro392Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,461,888 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000013 (1 hom.)
• Consequence: TMPO NM_001032283.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.98
• 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: 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.137508).
• BS2: High AC in GnomAdExome4 at 19 Unknown,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001032283.3. 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
	TMPO	NM_001032283.3	MANE Select	c.1174C>T	p.Pro392Ser	missense	Exon 9 of 9	NP_001027454.1	P42167-1
	TMPO	NM_001307975.2		c.1054C>T	p.Pro352Ser	missense	Exon 8 of 8	NP_001294904.1	G5E972
	TMPO	NM_001032284.3		c.847C>T	p.Pro283Ser	missense	Exon 6 of 6	NP_001027455.1	P42167-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPO	ENST00000556029.6	TSL:1 MANE Select	c.1174C>T	p.Pro392Ser	missense	Exon 9 of 9	ENSP00000450627.1	P42167-1
	TMPO	ENST00000393053.6	TSL:1	c.847C>T	p.Pro283Ser	missense	Exon 6 of 6	ENSP00000376773.2	P42167-2
	TMPO	ENST00000715724.1		c.1174C>T	p.Pro392Ser	missense	Exon 9 of 9	ENSP00000520506.1	P42167-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000318 AC: 8 AN: 251450 AF XY: 0.0000515

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461888 Hom.: 1 Cov.: 31 AF XY: 0.0000206 AC XY: 15 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 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: 39698

South Asian (SAS) AF: 0.000220 AC: 19 AN: 86256

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 Cov.: 33

ExAC AF: 0.0000165 AC: 2

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	-0.27	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.066	T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.081
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.2	L
PhyloP100		2.0
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.049
Sift	Benign	0.16	T
Sift4G	Benign	0.40	T
Polyphen		0.037	B
Vest4		0.064
MutPred		0.35		Gain of sheet (P = 0.0043)
MVP		0.55
ClinPred		0.10	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=76/24	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs727504622; hg19: chr12-98941445;