rs150016894

chr21-44567937-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_144991.3(TSPEAR):c.151G>A(p.Val51Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00167 in 1,593,350 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (3 hom.)
• Consequence: TSPEAR NM_144991.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.241

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01081568).
• BP6: Variant 21-44567937-C-T is Benign according to our data. Variant chr21-44567937-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 228047.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1}. Variant chr21-44567937-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSPEAR	NM_144991.3	c.151G>A	p.Val51Ile	missense_variant	2/12	ENST00000323084.9
TSPEAR	NM_001272037.2	c.-54G>A		5_prime_UTR_variant	3/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSPEAR	ENST00000323084.9	c.151G>A	p.Val51Ile	missense_variant	2/12	1	NM_144991.3	P1
TSPEAR	ENST00000397916.1	n.106G>A		non_coding_transcript_exon_variant	2/11	1
TSPEAR	ENST00000642437.1	c.*96G>A		3_prime_UTR_variant, NMD_transcript_variant	3/13

Frequencies

GnomAD3 genomes AF: 0.00129 AC: 196 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00234

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00105 AC: 255 AN: 242878 Hom.: 0 AF XY: 0.00113 AC XY: 148 AN XY: 131308

Gnomad AFR exome AF: 0.000373

Gnomad AMR exome AF: 0.000777

Gnomad ASJ exome AF: 0.000105

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000513

Gnomad FIN exome AF: 0.000328

Gnomad NFE exome AF: 0.00173

Gnomad OTH exome AF: 0.00155

GnomAD4 exome AF: 0.00171 AC: 2470 AN: 1441078 Hom.: 3 Cov.: 30 AF XY: 0.00170 AC XY: 1217 AN XY: 714966

Gnomad4 AFR exome AF: 0.000333

Gnomad4 AMR exome AF: 0.000978

Gnomad4 ASJ exome AF: 0.0000392

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000788

Gnomad4 FIN exome AF: 0.000396

Gnomad4 NFE exome AF: 0.00205

Gnomad4 OTH exome AF: 0.00121

GnomAD4 genome AF: 0.00129 AC: 196 AN: 152272 Hom.: 0 Cov.: 32 AF XY: 0.00113 AC XY: 84 AN XY: 74468

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000849

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00234

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00168 Hom.: 1

Bravo AF: 0.00107

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000980 AC: 119

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 04, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 10, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 20, 2017	- -

TSPEAR-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 16, 2024

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). -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 04, 2015

p.Val51Ile in exon 2 of TSPEAR: This variant is not expected to have clinical si gnificance due to a lack of conservation across species, including mammals. Of n ote, 6 mammals have an isoleucine (Ile) at this position. In addition, computati onal prediction tools do not suggest a high likelihood of impact to the protein. Furthermore, this variant has been identified in 0.15% (97/65584) of European c hromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute .org; dbSNP rs150016894). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.75
Cadd	Benign	0.20
Dann	Benign	0.74
DEOGEN2	Benign	0.040	T;T
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0074	N
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.35	T
Sift4G	Benign	0.69	T;T
Polyphen		0.0020	B;B
Vest4		0.11
MVP		0.014
MPC		0.044
ClinPred		0.00087	T
GERP RS		2.4
Varity_R		0.029
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs150016894; hg19: chr21-45987821;