rs148967240

chr21-44533809-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_144991.3(TSPEAR):c.418G>A(p.Ala140Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000227 in 1,612,380 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A140D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 29)
  • Exomes 𝑓: 0.00021 (1 hom.)
• Consequence: TSPEAR NM_144991.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 0.245

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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.01668325).
• BP6: Variant 21-44533809-C-T is Benign according to our data. Variant chr21-44533809-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 229378.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSPEAR	NM_144991.3	c.418G>A	p.Ala140Thr	missense_variant	3/12	ENST00000323084.9
TSPEAR	NM_001272037.2	c.214G>A	p.Ala72Thr	missense_variant	4/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSPEAR	ENST00000323084.9	c.418G>A	p.Ala140Thr	missense_variant	3/12	1	NM_144991.3	P1
TSPEAR	ENST00000397916.1	n.373G>A		non_coding_transcript_exon_variant	3/11	1
TSPEAR	ENST00000642437.1	c.*363G>A		3_prime_UTR_variant, NMD_transcript_variant	4/13

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 152128 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000470 AC: 116 AN: 246908 Hom.: 0 AF XY: 0.000297 AC XY: 40 AN XY: 134650

Gnomad AFR exome AF: 0.000382

Gnomad AMR exome AF: 0.00250

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000172

Gnomad OTH exome AF: 0.000828

GnomAD4 exome AF: 0.000209 AC: 305 AN: 1460252 Hom.: 1 Cov.: 32 AF XY: 0.000197 AC XY: 143 AN XY: 726428

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.00255

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000145

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.000401 AC: 61 AN: 152128 Hom.: 0 Cov.: 29 AF XY: 0.000538 AC XY: 40 AN XY: 74296

Gnomad4 AFR AF: 0.000314

Gnomad4 AMR AF: 0.00242

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000135 Hom.: 0

Bravo AF: 0.000548

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000348 AC: 42

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 04, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 11, 2024	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 18, 2015

Variant classified as Uncertain Significance - Favor Benign. The p.Ala140Thr var iant in TSPEAR has been previously reported by our laboratory in one individual with hearing loss, but a variant affecting the remaining copy of TSPEAR was not identified. This variant has been identified in 0.2% (26/11328) of Latino chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs148967240). Although this variant has been seen in the general populat ion, its frequency is not high enough to rule out a pathogenic role. Computation al prediction tools and conservation analysis suggest that the p.Ala140Thr varia nt may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the p. Ala140Thr variant is uncertain, these data suggest that it is more likely to be benign. -

TSPEAR-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 17, 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	0.078
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	12
Dann	Uncertain	0.99
DEOGEN2	Benign	0.025	T;T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.30	N
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.017	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	0.99	N;N
PrimateAI	Uncertain	0.60	T
Polyphen		0.074	B;B
Vest4		0.22
MVP		0.055
MPC		0.050
ClinPred		0.015	T
GERP RS		2.7
Varity_R		0.040
gMVP		0.38

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: rs148967240; hg19: chr21-45953692; COSMIC: COSV59951251;