rs112475937

Positions:

• chr12-98546355-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001032283.3(TMPO):​c.991-4T>C variant causes a splice region, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001126
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.17

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 -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. Variant chr12-98546355-T-C is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
TMPO	NM_001032283.3	c.991-4T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000556029.6
TMPO	NM_001032284.3	c.664-4T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
TMPO	NM_001307975.2	c.871-4T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
TMPO	XM_005269132.5	c.775-4T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMPO	ENST00000556029.6	c.991-4T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001032283.3

Frequencies

GnomAD3 genomes AF: 0.0176 AC: 2674 AN: 152132 Hom.: 74 Cov.: 32

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

GnomAD3 exomes AF: 0.00466 AC: 1171 AN: 251158 Hom.: 37 AF XY: 0.00356 AC XY: 484 AN XY: 135766

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 SAS exome AF: 0.000163

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

Gnomad4 AFR exome AF: 0.0628

Gnomad4 AMR exome AF: 0.00461

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000256

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000251

Gnomad4 OTH exome AF: 0.00461

GnomAD4 genome AF: 0.0176 AC: 2680 AN: 152250 Hom.: 74 Cov.: 32 AF XY: 0.0172 AC XY: 1281 AN XY: 74452

Gnomad4 AFR AF: 0.0595

Gnomad4 AMR AF: 0.00994

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.00809 Hom.: 15

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

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 11, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 19, 2012

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
RBP_binding_hub_radar		0.77
RBP_regulation_power_radar		1.9

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

LitVar

Other links and lift over

dbSNP: rs112475937; hg19: chr12-98940133;