rs112475937

Variant names:

• chr12-98546355-T-C
• rs112475937
• NM_001032283.3:c.991-4T>C

Variant summary

Our verdict is Benign. The variant received -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, 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: Splicing: ADA: 0.0001126
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.17
• Publications: 1 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 (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 VariationId 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.

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.991-4T>C		splice_region intron	N/A	NP_001027454.1	P42167-1
	TMPO	NM_001307975.2		c.871-4T>C		splice_region intron	N/A	NP_001294904.1	G5E972
	TMPO	NM_001032284.3		c.664-4T>C		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.991-4T>C		splice_region intron	N/A	ENSP00000450627.1	P42167-1
	TMPO	ENST00000393053.6	TSL:1	c.664-4T>C		splice_region intron	N/A	ENSP00000376773.2	P42167-2
	TMPO	ENST00000715724.1		c.991-4T>C		splice_region intron	N/A	ENSP00000520506.1	P42167-1

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

GnomAD2 exomes AF: 0.00466 AC: 1171 AN: 251158 AF XY: 0.00356

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

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

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

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

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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

Other links and lift over

dbSNP: rs112475937; hg19: chr12-98940133;