12-98516115-C-T

Variant names:

• chr12-98516115-C-T
• rs730880228
• NM_001032283.3:c.248C>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.248C>T​(p.Ala83Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000157 in 1,527,602 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A83T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: TMPO NM_001032283.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 0.435
• Publications: 1 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-AS1 (HGNC:44158): (TMPO antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.083732545).
• BS2: High AC in GnomAdExome4 at 21 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.248C>T	p.Ala83Val	missense	Exon 1 of 9	NP_001027454.1
	TMPO	NM_003276.2		c.248C>T	p.Ala83Val	missense	Exon 1 of 4	NP_003267.1
	TMPO	NM_001307975.2		c.248C>T	p.Ala83Val	missense	Exon 1 of 8	NP_001294904.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPO	ENST00000556029.6	TSL:1 MANE Select	c.248C>T	p.Ala83Val	missense	Exon 1 of 9	ENSP00000450627.1
	TMPO	ENST00000266732.8	TSL:1	c.248C>T	p.Ala83Val	missense	Exon 1 of 4	ENSP00000266732.4
	TMPO	ENST00000393053.6	TSL:1	c.248C>T	p.Ala83Val	missense	Exon 1 of 6	ENSP00000376773.2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152166 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000250 AC: 3 AN: 120096 AF XY: 0.0000147

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: 0.0000153 AC: 21 AN: 1375436 Hom.: 0 Cov.: 31 AF XY: 0.0000162 AC XY: 11 AN XY: 679050

African (AFR) AF: 0.00 AC: 0 AN: 29786

American (AMR) AF: 0.00 AC: 0 AN: 32290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23354

East Asian (EAS) AF: 0.00 AC: 0 AN: 35142

South Asian (SAS) AF: 0.000104 AC: 8 AN: 76922

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37722

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5140

European-Non Finnish (NFE) AF: 0.0000111 AC: 12 AN: 1077914

Other (OTH) AF: 0.0000175 AC: 1 AN: 57166

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152166 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74324

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000505 AC: 5

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Loeys-Dietz syndrome 2 (1)
-	1	-	not provided (1)
-	1	-	not specified (1)
-	1	-	Primary familial hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.0076	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.46	D
MetaRNN	Benign	0.084	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.20	N
PhyloP100		0.43
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	0.51	N
REVEL	Benign	0.043
Sift	Benign	0.21	T
Sift4G	Benign	0.36	T
Polyphen		0.0	B
Vest4		0.16
MutPred		0.32		Gain of catalytic residue at S87 (P = 0)
MVP		0.31
MPC		0.068
ClinPred		0.057	T
GERP RS		1.8
PromoterAI		0.019	Neutral
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		3.2
Varity_R		0.031
gMVP		0.097
Mutation Taster		=95/5	polymorphism

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: rs730880228; hg19: chr12-98909893;