21-44533809-C-A

Variant names:

• chr21-44533809-C-A
• NM_144991.3:c.418G>T

Variant summary

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

The NM_144991.3(TSPEAR):​c.418G>T​(p.Ala140Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,252 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TSPEAR NM_144991.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.245

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13647726).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSPEAR	NM_144991.3	c.418G>T	p.Ala140Ser	missense_variant	Exon 3 of 12	ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2	c.214G>T	p.Ala72Ser	missense_variant	Exon 4 of 13		NP_001258966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSPEAR	ENST00000323084.9	c.418G>T	p.Ala140Ser	missense_variant	Exon 3 of 12	1	NM_144991.3	ENSP00000321987.4
TSPEAR	ENST00000397916.1	n.373G>T		non_coding_transcript_exon_variant	Exon 3 of 11	1
TSPEAR	ENST00000642437.1	n.*363G>T		non_coding_transcript_exon_variant	Exon 4 of 13			ENSP00000496535.1
TSPEAR	ENST00000642437.1	n.*363G>T		3_prime_UTR_variant	Exon 4 of 13			ENSP00000496535.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460252 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726428

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	6.5
DANN	Benign	0.93
DEOGEN2	Benign	0.020	T;T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.69	.;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.95	L;L
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	0.15	.;N
REVEL	Benign	0.011
Sift	Benign	0.20	.;T
Sift4G	Benign	0.30	.;T
Polyphen		0.035	B;B
Vest4		0.13
MutPred		0.33		Loss of catalytic residue at A140 (P = 0.0501);Loss of catalytic residue at A140 (P = 0.0501);
MVP		0.048
MPC		0.048
ClinPred		0.12	T
GERP RS		2.7
Varity_R		0.044
gMVP		0.34

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-45953692;