21-44499814-A-C

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.1979T>G(p.Leu660Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000779 in 1,578,904 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: TSPEAR NM_144991.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 4.33

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=0.015064806).
• BP6: Variant 21-44499814-A-C is Benign according to our data. Variant chr21-44499814-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1186484.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSPEAR	NM_144991.3	c.1979T>G	p.Leu660Arg	missense_variant	12/12	ENST00000323084.9
TSPEAR	NM_001272037.2	c.1775T>G	p.Leu592Arg	missense_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSPEAR	ENST00000323084.9	c.1979T>G	p.Leu660Arg	missense_variant	12/12	1	NM_144991.3	P1
TSPEAR	ENST00000642437.1	c.*1924T>G		3_prime_UTR_variant, NMD_transcript_variant	13/13

Frequencies

GnomAD3 genomes AF: 0.000447 AC: 68 AN: 152122 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000992 AC: 19 AN: 191516 Hom.: 0 AF XY: 0.0000774 AC XY: 8 AN XY: 103318

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.0000341

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: 0.0000124

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000357 AC: 51 AN: 1426666 Hom.: 0 Cov.: 31 AF XY: 0.0000326 AC XY: 23 AN XY: 706602

Gnomad4 AFR exome AF: 0.00114

Gnomad4 AMR exome AF: 0.0000497

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000183

Gnomad4 OTH exome AF: 0.000170

GnomAD4 genome AF: 0.000473 AC: 72 AN: 152238 Hom.: 0 Cov.: 33 AF XY: 0.000497 AC XY: 37 AN XY: 74440

Gnomad4 AFR AF: 0.00161

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000147 Hom.: 0

Bravo AF: 0.000540

ESP6500AA AF: 0.00229 AC: 10

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000100 AC: 12

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 30, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 27, 2023	This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 660 of the TSPEAR protein (p.Leu660Arg). This variant is present in population databases (rs140818230, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with TSPEAR-related conditions. ClinVar contains an entry for this variant (Variation ID: 1186484). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TSPEAR protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 22, 2023

The c.1979T>G (p.L660R) alteration is located in exon 12 (coding exon 12) of the TSPEAR gene. This alteration results from a T to G substitution at nucleotide position 1979, causing the leucine (L) at amino acid position 660 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.49
Cadd	Uncertain	23
Dann	Benign	0.97
DEOGEN2	Benign	0.088	T;T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.063
FATHMM_MKL	Uncertain	0.81	D
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.015	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.57	T
Polyphen		0.071	B;B
Vest4		0.31
MVP		0.040
MPC		0.068
ClinPred		0.085	T
GERP RS		3.2
Varity_R		0.21
gMVP		0.65

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: rs140818230; hg19: chr21-45919697;