12-98546450-AT-ATT

Variant names:

• chr12-98546450-A-AT
• rs34449077
• NM_001032283.3:c.1079+5dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001032283.3(TMPO):​c.1079+5dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0822 in 1,561,232 control chromosomes in the GnomAD database, including 6,602 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.070 (579 hom., cov: 31)
  • Exomes 𝑓: 0.084 (6023 hom.)
• Consequence: TMPO NM_001032283.3 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.24
• Publications: 5 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: AD, Unknown Classification: SUPPORTIVE, NO_KNOWN Submitted by: Orphanet, ClinGen
• 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 -16 ACMG points.

• BP6: Variant 12-98546450-A-AT is Benign according to our data. Variant chr12-98546450-A-AT is described in ClinVar as Benign. ClinVar VariationId is 43691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.224 is higher than 0.05.

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.1079+5dupT		splice_region intron	N/A	NP_001027454.1	P42167-1
	TMPO	NM_001307975.2		c.959+5dupT		splice_region intron	N/A	NP_001294904.1	G5E972
	TMPO	NM_001032284.3		c.752+5dupT		splice_region intron	N/A	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.1079+3_1079+4insT		splice_region intron	N/A	ENSP00000450627.1	P42167-1
	TMPO	ENST00000393053.6	TSL:1	c.752+3_752+4insT		splice_region intron	N/A	ENSP00000376773.2	P42167-2
	TMPO	ENST00000715724.1		c.1079+3_1079+4insT		splice_region intron	N/A	ENSP00000520506.1	P42167-1

Frequencies

GnomAD3 genomes AF: 0.0702 AC: 10684 AN: 152168 Hom.: 579 Cov.: 31

Gnomad AFR AF: 0.0147

Gnomad AMI AF: 0.0636

Gnomad AMR AF: 0.0605

Gnomad ASJ AF: 0.0642

Gnomad EAS AF: 0.236

Gnomad SAS AF: 0.0877

Gnomad FIN AF: 0.135

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0828

Gnomad OTH AF: 0.0650

GnomAD2 exomes AF: 0.0841 AC: 21105 AN: 251054 AF XY: 0.0855

Gnomad AFR exome AF: 0.0132

Gnomad AMR exome AF: 0.0374

Gnomad ASJ exome AF: 0.0673

Gnomad EAS exome AF: 0.242

Gnomad FIN exome AF: 0.131

Gnomad NFE exome AF: 0.0761

Gnomad OTH exome AF: 0.0760

GnomAD4 exome AF: 0.0836 AC: 117727 AN: 1408946 Hom.: 6023 Cov.: 24 AF XY: 0.0843 AC XY: 59355 AN XY: 704272

African (AFR) AF: 0.0115 AC: 372 AN: 32456

American (AMR) AF: 0.0393 AC: 1754 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.0662 AC: 1706 AN: 25784

East Asian (EAS) AF: 0.259 AC: 10187 AN: 39338

South Asian (SAS) AF: 0.0829 AC: 7056 AN: 85110

European-Finnish (FIN) AF: 0.131 AC: 6973 AN: 53358

Middle Eastern (MID) AF: 0.0668 AC: 380 AN: 5690

European-Non Finnish (NFE) AF: 0.0790 AC: 84081 AN: 1064014

Other (OTH) AF: 0.0891 AC: 5218 AN: 58544

GnomAD4 genome AF: 0.0701 AC: 10678 AN: 152286 Hom.: 579 Cov.: 31 AF XY: 0.0731 AC XY: 5444 AN XY: 74456

African (AFR) AF: 0.0147 AC: 612 AN: 41576

American (AMR) AF: 0.0605 AC: 926 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0642 AC: 223 AN: 3472

East Asian (EAS) AF: 0.235 AC: 1220 AN: 5186

South Asian (SAS) AF: 0.0876 AC: 423 AN: 4828

European-Finnish (FIN) AF: 0.135 AC: 1428 AN: 10598

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0828 AC: 5634 AN: 68008

Other (OTH) AF: 0.0639 AC: 135 AN: 2114

Alfa AF: 0.0740 Hom.: 87

Bravo AF: 0.0610

Asia WGS AF: 0.128 AC: 444 AN: 3478

EpiCase AF: 0.0798

EpiControl AF: 0.0768

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2
Mutation Taster		=76/24	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs34449077; hg19: chr12-98940228; COSMIC: COSV107448241;