rs112475937

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001032283.3(TMPO):​c.991-4T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00348 in 1,599,648 control chromosomes in the GnomAD database, including 141 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 74 hom., cov: 32)
Exomes 𝑓: 0.0020 ( 67 hom. )

Consequence

TMPO
NM_001032283.3 splice_region, intron

Scores

2
Splicing: ADA: 0.0001126
2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.17

Publications

1 publications found
Variant links:
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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.69).
BP6
Variant 12-98546355-T-C is Benign according to our data. Variant chr12-98546355-T-C is described in ClinVar as [Benign]. Clinvar id is 43695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0576 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TMPONM_001032283.3 linkc.991-4T>C splice_region_variant, intron_variant Intron 7 of 8 ENST00000556029.6 NP_001027454.1 P42167-1A0A024RBE7Q59G12
TMPONM_001307975.2 linkc.871-4T>C splice_region_variant, intron_variant Intron 6 of 7 NP_001294904.1 P42167G5E972
TMPONM_001032284.3 linkc.664-4T>C splice_region_variant, intron_variant Intron 4 of 5 NP_001027455.1 P42167-2A0A024RBH7Q59G12
TMPOXM_005269132.5 linkc.775-4T>C splice_region_variant, intron_variant Intron 5 of 6 XP_005269189.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TMPOENST00000556029.6 linkc.991-4T>C splice_region_variant, intron_variant Intron 7 of 8 1 NM_001032283.3 ENSP00000450627.1 P42167-1

Frequencies

GnomAD3 genomes
AF:
0.0176
AC:
2674
AN:
152132
Hom.:
74
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0596
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00995
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000622
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.000382
Gnomad OTH
AF:
0.0120
GnomAD2 exomes
AF:
0.00466
AC:
1171
AN:
251158
AF XY:
0.00356
show subpopulations
Gnomad AFR exome
AF:
0.0597
Gnomad AMR exome
AF:
0.00405
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000396
Gnomad OTH exome
AF:
0.00213
GnomAD4 exome
AF:
0.00199
AC:
2880
AN:
1447398
Hom.:
67
Cov.:
28
AF XY:
0.00177
AC XY:
1273
AN XY:
721056
show subpopulations
African (AFR)
AF:
0.0628
AC:
2083
AN:
33150
American (AMR)
AF:
0.00461
AC:
206
AN:
44690
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26012
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39538
South Asian (SAS)
AF:
0.000256
AC:
22
AN:
85904
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53390
Middle Eastern (MID)
AF:
0.00305
AC:
17
AN:
5574
European-Non Finnish (NFE)
AF:
0.000251
AC:
276
AN:
1099248
Other (OTH)
AF:
0.00461
AC:
276
AN:
59892
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.476
Heterozygous variant carriers
0
128
256
384
512
640
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
76
152
228
304
380
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0176
AC:
2680
AN:
152250
Hom.:
74
Cov.:
32
AF XY:
0.0172
AC XY:
1281
AN XY:
74452
show subpopulations
African (AFR)
AF:
0.0595
AC:
2472
AN:
41542
American (AMR)
AF:
0.00994
AC:
152
AN:
15294
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3464
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5184
South Asian (SAS)
AF:
0.000622
AC:
3
AN:
4822
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10604
Middle Eastern (MID)
AF:
0.00680
AC:
2
AN:
294
European-Non Finnish (NFE)
AF:
0.000382
AC:
26
AN:
68026
Other (OTH)
AF:
0.0118
AC:
25
AN:
2110
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.501
Heterozygous variant carriers
0
124
247
371
494
618
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
26
52
78
104
130
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00846
Hom.:
26
Bravo
AF:
0.0202
Asia WGS
AF:
0.00318
AC:
11
AN:
3478
EpiCase
AF:
0.000491
EpiControl
AF:
0.000415

ClinVar

Significance: Benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Jun 11, 2018
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:1
Mar 19, 2012
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

c.991-4T>C in Intron 07 of TMPO: This variant is not expected to have clinical s ignificance because it is not located within the splice consensus sequence and h as been identified in 5.4% (201/3738) of African American chromosomes from a bro ad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.ed u/EVS; dbSNP rs112475937). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.69
CADD
Benign
5.1
DANN
Benign
0.74
PhyloP100
-1.2
RBP_binding_hub_radar
0.77
RBP_regulation_power_radar
1.9
Mutation Taster
=100/0
polymorphism (auto)

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.00011
dbscSNV1_RF
Benign
0.0

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

Publications

Other links and lift over

dbSNP: rs112475937; hg19: chr12-98940133; API