21-44522077-A-T

Variant names:

• chr21-44522077-A-T
• NM_144991.3:c.1372T>A
• TSPEAR p.Trp458Arg

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_144991.3(TSPEAR):​c.1372T>A​(p.Trp458Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W458G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSPEAR NM_144991.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.74
• Publications: 0 publications found

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-AS1 (HGNC:1271): (TSPEAR antisense RNA 1)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144991.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSPEAR	NM_144991.3	MANE Select	c.1372T>A	p.Trp458Arg	missense	Exon 9 of 12	NP_659428.2
	TSPEAR	NM_001272037.2		c.1168T>A	p.Trp390Arg	missense	Exon 10 of 13	NP_001258966.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSPEAR	ENST00000323084.9	TSL:1 MANE Select	c.1372T>A	p.Trp458Arg	missense	Exon 9 of 12	ENSP00000321987.4	Q8WU66-1
	TSPEAR	ENST00000397916.1	TSL:1	n.1327T>A		non_coding_transcript_exon	Exon 9 of 11
	TSPEAR	ENST00000943283.1		c.1372T>A	p.Trp458Arg	missense	Exon 9 of 13	ENSP00000613342.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		6.7
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-10	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0090	D
Sift4G	Pathogenic	0.0	D
Varity_R		0.89
gMVP		0.92
Mutation Taster		=14/86	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr21-45941960;