21-44521956-C-T

Position:

• chr21-44521956-C-T

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:16428): (TSPEAR antisense RNA 2)

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/exons	MANE	Protein	UniProt
TSPEAR	NM_144991.3	c.1493G>A	p.Gly498Asp	missense_variant	9/12	ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2	c.1289G>A	p.Gly430Asp	missense_variant	10/13		NP_001258966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSPEAR	ENST00000323084.9	c.1493G>A	p.Gly498Asp	missense_variant	9/12	1	NM_144991.3	ENSP00000321987	P1
TSPEAR	ENST00000397916.1	n.1448G>A		non_coding_transcript_exon_variant	9/11	1
TSPEAR-AS2	ENST00000465978.1	n.217-3868C>T		intron_variant, non_coding_transcript_variant		5
TSPEAR	ENST00000642437.1	c.*1438G>A		3_prime_UTR_variant, NMD_transcript_variant	10/13			ENSP00000496535

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

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 10, 2016

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
MutationTaster	Benign	1.0	D;D
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;