rs398039979

chr12-98546450-A-ATchr12-98546450-AT-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001032283.3(TMPO):c.1079+5dup variant causes a splice donor 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_donor_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.24

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.

• BP6: Variant 12-98546450-A-AT is Benign according to our data. Variant chr12-98546450-A-AT is described in ClinVar as [Benign]. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMPO	NM_001032283.3	c.1079+5dup		splice_donor_region_variant, intron_variant		ENST00000556029.6
TMPO	NM_001032284.3	c.752+5dup		splice_donor_region_variant, intron_variant
TMPO	NM_001307975.2	c.959+5dup		splice_donor_region_variant, intron_variant
TMPO	XM_005269132.5	c.863+5dup		splice_donor_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMPO	ENST00000556029.6	c.1079+5dup		splice_donor_region_variant, intron_variant		1	NM_001032283.3

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

GnomAD3 exomes AF: 0.0841 AC: 21105 AN: 251054 Hom.: 1274 AF XY: 0.0855 AC XY: 11602 AN XY: 135674

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 SAS exome AF: 0.0824

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

Gnomad4 AFR exome AF: 0.0115

Gnomad4 AMR exome AF: 0.0393

Gnomad4 ASJ exome AF: 0.0662

Gnomad4 EAS exome AF: 0.259

Gnomad4 SAS exome AF: 0.0829

Gnomad4 FIN exome AF: 0.131

Gnomad4 NFE exome AF: 0.0790

Gnomad4 OTH exome AF: 0.0891

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

Gnomad4 AFR AF: 0.0147

Gnomad4 AMR AF: 0.0605

Gnomad4 ASJ AF: 0.0642

Gnomad4 EAS AF: 0.235

Gnomad4 SAS AF: 0.0876

Gnomad4 FIN AF: 0.135

Gnomad4 NFE AF: 0.0828

Gnomad4 OTH AF: 0.0639

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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 20, 2012

1079+5_1079+6insT in intron 8 of TMPO: This variant is not expected to have clin ical significance because it has been identified in 24% (136/572) of Asian chrom osomes from a broad population by the 1000 Genomes project (dbSNP rs34449077 - l isted as 1079+3_1079+4insT; also under rs71305593). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 15, 2018

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs34449077; hg19: chr12-98940228;