rs17459334

Variant names:

• chr12-98534052-C-G
• rs17459334
• ENST00000266732.8:c.1795C>G

Your query was ambiguous. Multiple possible variants found:

• chr12-98534052-C-G
• chr12-98534052-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003276.2(TMPO):​c.1795C>G​(p.Gln599Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0918 in 1,608,298 control chromosomes in the GnomAD database, including 7,749 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q599H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.070 (532 hom., cov: 33)
  • Exomes 𝑓: 0.094 (7217 hom.)
• Consequence: TMPO NM_003276.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.19
• Publications: 22 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014932156).
• BP6: Variant 12-98534052-C-G is Benign according to our data. Variant chr12-98534052-C-G is described in ClinVar as Benign. ClinVar VariationId is 44667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.143 is higher than 0.05.

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+2214C>G		intron	N/A	NP_001027454.1	P42167-1
	TMPO	NM_003276.2		c.1795C>G	p.Gln599Glu	missense	Exon 4 of 4	NP_003267.1	P42166-1
	TMPO	NM_001307975.2		c.565+2214C>G		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.1795C>G	p.Gln599Glu	missense	Exon 4 of 4	ENSP00000266732.4	P42166-1
	TMPO	ENST00000556029.6	TSL:1 MANE Select	c.565+2214C>G		intron	N/A	ENSP00000450627.1	P42167-1
	TMPO	ENST00000393053.6	TSL:1	c.565+2214C>G		intron	N/A	ENSP00000376773.2	P42167-2

Frequencies

GnomAD3 genomes AF: 0.0703 AC: 10705 AN: 152206 Hom.: 530 Cov.: 33

Gnomad AFR AF: 0.0180

Gnomad AMI AF: 0.0593

Gnomad AMR AF: 0.0604

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.152

Gnomad FIN AF: 0.105

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.0962

Gnomad OTH AF: 0.0692

GnomAD2 exomes AF: 0.0854 AC: 21351 AN: 249932 AF XY: 0.0926

Gnomad AFR exome AF: 0.0149

Gnomad AMR exome AF: 0.0405

Gnomad ASJ exome AF: 0.108

Gnomad EAS exome AF: 0.000653

Gnomad FIN exome AF: 0.101

Gnomad NFE exome AF: 0.0982

Gnomad OTH exome AF: 0.0900

GnomAD4 exome AF: 0.0940 AC: 136915 AN: 1455974 Hom.: 7217 Cov.: 33 AF XY: 0.0967 AC XY: 69870 AN XY: 722910

African (AFR) AF: 0.0157 AC: 522 AN: 33344

American (AMR) AF: 0.0426 AC: 1900 AN: 44594

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 2696 AN: 26032

East Asian (EAS) AF: 0.000582 AC: 23 AN: 39524

South Asian (SAS) AF: 0.159 AC: 13654 AN: 86124

European-Finnish (FIN) AF: 0.103 AC: 5495 AN: 53304

Middle Eastern (MID) AF: 0.125 AC: 721 AN: 5746

European-Non Finnish (NFE) AF: 0.0962 AC: 106507 AN: 1107236

Other (OTH) AF: 0.0898 AC: 5397 AN: 60070

GnomAD4 genome AF: 0.0702 AC: 10697 AN: 152324 Hom.: 532 Cov.: 33 AF XY: 0.0712 AC XY: 5303 AN XY: 74476

African (AFR) AF: 0.0180 AC: 747 AN: 41588

American (AMR) AF: 0.0603 AC: 923 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 384 AN: 3470

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5188

South Asian (SAS) AF: 0.152 AC: 734 AN: 4826

European-Finnish (FIN) AF: 0.105 AC: 1119 AN: 10610

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.0962 AC: 6544 AN: 68022

Other (OTH) AF: 0.0685 AC: 145 AN: 2116

Alfa AF: 0.0920 Hom.: 516

Bravo AF: 0.0628

TwinsUK AF: 0.0933 AC: 346

ALSPAC AF: 0.0846 AC: 326

ESP6500AA AF: 0.0216 AC: 95

ESP6500EA AF: 0.0965 AC: 830

ExAC AF: 0.0872 AC: 10583

Asia WGS AF: 0.0630 AC: 219 AN: 3478

EpiCase AF: 0.102

EpiControl AF: 0.102

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	Loeys-Dietz syndrome 2 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L
PhyloP100		2.2
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.15
Sift	Benign	0.10	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.92	P
Vest4		0.12
MPC		0.11
ClinPred		0.025	T
GERP RS		6.0
Varity_R		0.15
gMVP		0.039
Mutation Taster		=97/3	polymorphism (auto)

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: rs17459334; hg19: chr12-98927830; COSMIC: COSV54123248; COSMIC: COSV54123248;