21-44499787-C-G

Variant names:

• chr21-44499787-C-G
• NM_144991.3:c.2006G>C

Variant summary

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

The NM_144991.3(TSPEAR):​c.2006G>C​(p.Arg669Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000708 in 1,413,126 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R669H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: TSPEAR NM_144991.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.150

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=0.07648477).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSPEAR	NM_144991.3	c.2006G>C	p.Arg669Pro	missense_variant	Exon 12 of 12	ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2	c.1802G>C	p.Arg601Pro	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.2006G>C	p.Arg669Pro	missense_variant	Exon 12 of 12	1	NM_144991.3	ENSP00000321987.4
TSPEAR	ENST00000642437.1	n.*1951G>C		non_coding_transcript_exon_variant	Exon 13 of 13			ENSP00000496535.1
TSPEAR	ENST00000642437.1	n.*1951G>C		3_prime_UTR_variant	Exon 13 of 13			ENSP00000496535.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.08e-7 AC: 1 AN: 1413126 Hom.: 0 Cov.: 31 AF XY: 0.00000143 AC XY: 1 AN XY: 698838

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: 0.0000124

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	Benign	0.23
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	11
DANN	Benign	0.97
DEOGEN2	Benign	0.026	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.59	.;T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.076	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.34	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.42	.;N
REVEL	Benign	0.034
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0	.;D
Polyphen		0.12	B;B
Vest4		0.11
MutPred		0.35		Loss of methylation at R669 (P = 0.0037);Loss of methylation at R669 (P = 0.0037);
MVP		0.030
MPC		0.33
ClinPred		0.42	T
GERP RS		-3.6
Varity_R		0.18
gMVP		0.51

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: chr21-45919670;