21-44521956-C-T

Variant names:

• chr21-44521956-C-T
• rs782040120
• NM_144991.3:c.1493G>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_144991.3(TSPEAR):​c.1493G>A​(p.Gly498Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSPEAR NM_144991.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.24

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]

TSPEAR-AS2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.895

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSPEAR	NM_144991.3	c.1493G>A	p.Gly498Asp	missense_variant	Exon 9 of 12	ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2	c.1289G>A	p.Gly430Asp	missense_variant	Exon 10 of 13		NP_001258966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSPEAR	ENST00000323084.9	c.1493G>A	p.Gly498Asp	missense_variant	Exon 9 of 12	1	NM_144991.3	ENSP00000321987.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 10, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Gly498Asp variant in TSPEAR has not been previously reported in individual s with hearing loss or in large population studies. Computational prediction too ls and conservation analysis suggest that the p.Gly498Asp variant may impact the protein, though this information is not predictive enough to determine pathogen icity. In summary, the clinical significance of the p.Gly498Asp variant is uncer tain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D;D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.89	.;D
M_CAP	Benign	0.025	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.0	M;M
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-4.4	.;D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0060	.;D
Sift4G	Pathogenic	0.0	.;D
Polyphen		1.0	D;D
Vest4		0.90
MutPred		0.73		Loss of catalytic residue at G498 (P = 0.0103);Loss of catalytic residue at G498 (P = 0.0103);
MVP		0.13
MPC		0.38
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.68
gMVP		0.66

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: rs782040120; hg19: chr21-45941839;