21-44567919-G-C

Variant names:

• chr21-44567919-G-C
• NM_144991.3:c.169C>G

Variant summary

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

The NM_144991.3(TSPEAR):​c.169C>G​(p.Arg57Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,158 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TSPEAR NM_144991.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.62

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.169C>G	p.Arg57Gly	missense_variant	Exon 2 of 12	ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2	c.-36C>G		5_prime_UTR_variant	Exon 3 of 13		NP_001258966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSPEAR	ENST00000323084.9	c.169C>G	p.Arg57Gly	missense_variant	Exon 2 of 12	1	NM_144991.3	ENSP00000321987.4
TSPEAR	ENST00000397916.1	n.124C>G		non_coding_transcript_exon_variant	Exon 2 of 11	1
TSPEAR	ENST00000642437.1	n.*114C>G		non_coding_transcript_exon_variant	Exon 3 of 13			ENSP00000496535.1
TSPEAR	ENST00000642437.1	n.*114C>G		3_prime_UTR_variant	Exon 3 of 13			ENSP00000496535.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453158 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 722422

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: 0.0000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.20	T;T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.78	.;T
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.43	T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.8	M;M
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-2.8	.;D
REVEL	Benign	0.15
Sift	Benign	0.070	.;T
Sift4G	Uncertain	0.014	D;D
Polyphen		0.77	P;P
Vest4		0.55
MutPred		0.59		Loss of methylation at R57 (P = 0.0109);Loss of methylation at R57 (P = 0.0109);
MVP		0.030
MPC		0.080
ClinPred		0.82	D
GERP RS		2.9
Varity_R		0.10
gMVP		0.62

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: chr21-45987803;