NM_001032283.3:c.859G>C

Variant names:

• chr12-98544517-G-C
• rs7133258
• NM_001032283.3:c.859G>C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001032283.3(TMPO):​c.859G>C​(p.Ala287Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 1,612,944 control chromosomes in the GnomAD database, including 141 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.0092 (17 hom., cov: 33)
  • Exomes 𝑓: 0.010 (124 hom.)
• Consequence: TMPO NM_001032283.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.99

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037781298).
• BP6: Variant 12-98544517-G-C is Benign according to our data. Variant chr12-98544517-G-C is described in ClinVar as [Benign]. Clinvar id is 43693.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-98544517-G-C is described in Lovd as [Benign].
• BS2: High AC in GnomAd4 at 1397 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPO	NM_001032283.3	c.859G>C	p.Ala287Pro	missense_variant	Exon 6 of 9	ENST00000556029.6	NP_001027454.1
TMPO	NM_001307975.2	c.739G>C	p.Ala247Pro	missense_variant	Exon 5 of 8		NP_001294904.1
TMPO	NM_001032284.3	c.664-1842G>C		intron_variant	Intron 4 of 5		NP_001027455.1
TMPO	XM_005269132.5	c.664-434G>C		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.859G>C	p.Ala287Pro	missense_variant	Exon 6 of 9	1	NM_001032283.3	ENSP00000450627.1

Frequencies

GnomAD3 genomes AF: 0.00919 AC: 1397 AN: 152078 Hom.: 17 Cov.: 33

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00980

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.0483

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0105

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.0104 AC: 2607 AN: 251018 Hom.: 31 AF XY: 0.0102 AC XY: 1386 AN XY: 135760

Gnomad AFR exome AF: 0.00167

Gnomad AMR exome AF: 0.00202

Gnomad ASJ exome AF: 0.00695

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00134

Gnomad FIN exome AF: 0.0467

Gnomad NFE exome AF: 0.0117

Gnomad OTH exome AF: 0.00917

GnomAD4 exome AF: 0.0102 AC: 14901 AN: 1460750 Hom.: 124 Cov.: 31 AF XY: 0.00991 AC XY: 7199 AN XY: 726716

Gnomad4 AFR exome AF: 0.000987

Gnomad4 AMR exome AF: 0.00204

Gnomad4 ASJ exome AF: 0.00704

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00153

Gnomad4 FIN exome AF: 0.0448

Gnomad4 NFE exome AF: 0.0104

Gnomad4 OTH exome AF: 0.00795

GnomAD4 genome AF: 0.00918 AC: 1397 AN: 152194 Hom.: 17 Cov.: 33 AF XY: 0.0107 AC XY: 797 AN XY: 74398

Gnomad4 AFR AF: 0.00157

Gnomad4 AMR AF: 0.00360

Gnomad4 ASJ AF: 0.00980

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.0483

Gnomad4 NFE AF: 0.0105

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00923 Hom.: 2

Bravo AF: 0.00523

TwinsUK AF: 0.0105 AC: 39

ALSPAC AF: 0.00804 AC: 31

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00988 AC: 85

ExAC AF: 0.0102 AC: 1236

Asia WGS AF: 0.00173 AC: 6 AN: 3474

EpiCase AF: 0.00857

EpiControl AF: 0.00907

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Nov 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TMPO: BP4, BS1, BS2 -

Aug 06, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:2

Dec 21, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ala287Pro in exon 6 of TMPO: This variant is not expected to have clinical signi ficance because it has been identified in 1.0% (85/8600) of European American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS; dbSNP rs7133258). Ala287Pro in exon 6 of TMPO (rs713 3258; allele frequency= 1.0%, 85/8600) ** -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

TMPO-related disorder Benign:1

Aug 30, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.011	T;T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.83	T;T
MetaRNN	Benign	0.0038	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L;.
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.067
Sift	Benign	0.21	T;T
Sift4G	Benign	0.21	T;T
Polyphen		0.93	P;.
Vest4		0.17
ClinPred		0.012	T
GERP RS		4.7

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs7133258; hg19: chr12-98938295;