21-44499828-G-T

Variant names:

• chr21-44499828-G-T
• rs781886235
• NM_144991.3:c.1965C>A

Variant summary

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

The NM_144991.3(TSPEAR):​c.1965C>A​(p.Ser655Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TSPEAR NM_144991.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00900

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSPEAR	NM_144991.3	c.1965C>A	p.Ser655Arg	missense_variant	Exon 12 of 12	ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2	c.1761C>A	p.Ser587Arg	missense_variant	Exon 13 of 13		NP_001258966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSPEAR	ENST00000323084.9	c.1965C>A	p.Ser655Arg	missense_variant	Exon 12 of 12	1	NM_144991.3	ENSP00000321987.4
TSPEAR	ENST00000642437.1	n.*1910C>A		non_coding_transcript_exon_variant	Exon 13 of 13			ENSP00000496535.1
TSPEAR	ENST00000642437.1	n.*1910C>A		3_prime_UTR_variant	Exon 13 of 13			ENSP00000496535.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1435652 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 711962

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.087	T;T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.38	N
LIST_S2	Uncertain	0.94	.;D
M_CAP	Benign	0.068	D
MetaRNN	Uncertain	0.46	T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.4	M;M
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-2.1	.;N
REVEL	Uncertain	0.44
Sift	Uncertain	0.0080	.;D
Sift4G	Uncertain	0.0040	.;D
Polyphen		1.0	D;D
Vest4		0.84
MutPred		0.54		Gain of MoRF binding (P = 0.0186);Gain of MoRF binding (P = 0.0186);
MVP		0.092
MPC		0.33
ClinPred		0.99	D
GERP RS		-8.2
Varity_R		0.56
gMVP		0.71

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: rs781886235; hg19: chr21-45919711;