21-44533808-G-A

Position:

• chr21-44533808-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_144991.3(TSPEAR):​c.419C>T​(p.Ala140Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 29)
• Consequence: TSPEAR NM_144991.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.22

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17987922).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSPEAR	NM_144991.3	c.419C>T	p.Ala140Val	missense_variant	3/12	ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2	c.215C>T	p.Ala72Val	missense_variant	4/13		NP_001258966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSPEAR	ENST00000323084.9	c.419C>T	p.Ala140Val	missense_variant	3/12	1	NM_144991.3	ENSP00000321987.4
TSPEAR	ENST00000397916.1	n.374C>T		non_coding_transcript_exon_variant	3/11	1
TSPEAR	ENST00000642437.1	n.*364C>T		non_coding_transcript_exon_variant	4/13			ENSP00000496535.1
TSPEAR	ENST00000642437.1	n.*364C>T		3_prime_UTR_variant	4/13			ENSP00000496535.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 29

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.026	T;T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.85	.;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.8	L;L
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.46	.;N
REVEL	Benign	0.061
Sift	Benign	0.26	.;T
Sift4G	Uncertain	0.048	.;D
Polyphen		0.040	B;B
Vest4		0.13
MutPred		0.42		Loss of loop (P = 0.0804);Loss of loop (P = 0.0804);
MVP		0.055
MPC		0.050
ClinPred		0.15	T
GERP RS		4.0
Varity_R		0.045
gMVP		0.43

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: rs147904376; hg19: chr21-45953691;