rs144586270

chr21-44533884-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_144991.3(TSPEAR):c.343G>A(p.Asp115Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000974 in 1,611,820 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D115D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0019 (2 hom., cov: 29)
  • Exomes 𝑓: 0.00088 (9 hom.)
• Consequence: TSPEAR NM_144991.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 0.775

Genes affected

TSPEAR (HGNC:1268): (thrombospondin type laminin G domain and EAR repeats) This gene encodes a protein that contains a N-terminal thrombospondin-type laminin G domain and several tandem arranged epilepsy-associated repeats (EARs). A mutation in this gene is the cause of autosomal recessive deafness-98. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Dec 2012]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003951758).
• BP6: Variant 21-44533884-C-T is Benign according to our data. Variant chr21-44533884-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 504830.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=2, Uncertain_significance=1}. Variant chr21-44533884-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000882 (1288/1460264) while in subpopulation MID AF= 0.0236 (136/5768). AF 95% confidence interval is 0.0204. There are 9 homozygotes in gnomad4_exome. There are 644 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSPEAR	NM_144991.3	c.343G>A	p.Asp115Asn	missense_variant	3/12	ENST00000323084.9
TSPEAR	NM_001272037.2	c.139G>A	p.Asp47Asn	missense_variant	4/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSPEAR	ENST00000323084.9	c.343G>A	p.Asp115Asn	missense_variant	3/12	1	NM_144991.3	P1
TSPEAR	ENST00000397916.1	n.298G>A		non_coding_transcript_exon_variant	3/11	1
TSPEAR	ENST00000642437.1	c.*288G>A		3_prime_UTR_variant, NMD_transcript_variant	4/13

Frequencies

GnomAD3 genomes AF: 0.00182 AC: 275 AN: 151440 Hom.: 1 Cov.: 29

Gnomad AFR AF: 0.00425

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00158

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000629

Gnomad FIN AF: 0.0000947

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000766

Gnomad OTH AF: 0.00530

GnomAD3 exomes AF: 0.00118 AC: 290 AN: 246454 Hom.: 0 AF XY: 0.00118 AC XY: 159 AN XY: 134350

Gnomad AFR exome AF: 0.00405

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.000403

Gnomad EAS exome AF: 0.0000547

Gnomad SAS exome AF: 0.00150

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00108

Gnomad OTH exome AF: 0.00298

GnomAD4 exome AF: 0.000882 AC: 1288 AN: 1460264 Hom.: 9 Cov.: 33 AF XY: 0.000887 AC XY: 644 AN XY: 726438

Gnomad4 AFR exome AF: 0.00544

Gnomad4 AMR exome AF: 0.00127

Gnomad4 ASJ exome AF: 0.000613

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00152

Gnomad4 FIN exome AF: 0.0000384

Gnomad4 NFE exome AF: 0.000571

Gnomad4 OTH exome AF: 0.00212

GnomAD4 genome AF: 0.00186 AC: 282 AN: 151556 Hom.: 2 Cov.: 29 AF XY: 0.00192 AC XY: 142 AN XY: 73990

Gnomad4 AFR AF: 0.00441

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000629

Gnomad4 FIN AF: 0.0000947

Gnomad4 NFE AF: 0.000766

Gnomad4 OTH AF: 0.00524

Alfa AF: 0.00129 Hom.: 1

Bravo AF: 0.00210

ESP6500AA AF: 0.00456 AC: 20

ESP6500EA AF: 0.000931 AC: 8

ExAC AF: 0.00115 AC: 139

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.00218

EpiControl AF: 0.00190

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 31, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 23, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	TSPEAR: BS1 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 26, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2014

Asp115Asn in exon 3 of TSPEAR: This variant is not expected to have clinical sig nificance because it has been identified in 0.5% (20/4388) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs144586270). -

TSPEAR-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 13, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.77
Cadd	Benign	13
Dann	Benign	0.95
DEOGEN2	Benign	0.038	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.13	N
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.0040	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.6	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.59	T
Sift4G	Benign	0.53	T;T
Polyphen		0.010	B;B
Vest4		0.21
MVP		0.014
MPC		0.063
ClinPred		0.0017	T
GERP RS		3.1
Varity_R		0.032
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs144586270; hg19: chr21-45953767;