21-44499887-C-T

Variant summary

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

The NM_144991.3(TSPEAR):c.1906G>A(p.Gly636Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000124 in 1,607,132 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00013 (1 hom.)
• Consequence: TSPEAR NM_144991.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.41

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/exons	MANE	UniProt
TSPEAR	NM_144991.3	c.1906G>A	p.Gly636Ser	missense_variant	12/12	ENST00000323084.9
TSPEAR	NM_001272037.2	c.1702G>A	p.Gly568Ser	missense_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSPEAR	ENST00000323084.9	c.1906G>A	p.Gly636Ser	missense_variant	12/12	1	NM_144991.3	P1
TSPEAR	ENST00000642437.1	c.*1851G>A		3_prime_UTR_variant, NMD_transcript_variant	13/13

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152218 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000688 AC: 16 AN: 232470 Hom.: 0 AF XY: 0.0000548 AC XY: 7 AN XY: 127736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000892

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000676

Gnomad FIN exome AF: 0.000201

Gnomad NFE exome AF: 0.0000682

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000126 AC: 183 AN: 1454914 Hom.: 1 Cov.: 31 AF XY: 0.000109 AC XY: 79 AN XY: 723550

Gnomad4 AFR exome AF: 0.0000302

Gnomad4 AMR exome AF: 0.0000452

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000469

Gnomad4 FIN exome AF: 0.0000969

Gnomad4 NFE exome AF: 0.000146

Gnomad4 OTH exome AF: 0.000150

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152218 Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6 AN XY: 74362

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000179 Hom.: 0

Bravo AF: 0.0000718

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000662 AC: 8

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 09, 2024

The c.1906G>A (p.G636S) alteration is located in exon 12 (coding exon 12) of the TSPEAR gene. This alteration results from a G to A substitution at nucleotide position 1906, causing the glycine (G) at amino acid position 636 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 30, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 636 of the TSPEAR protein (p.Gly636Ser). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TSPEAR protein function. ClinVar contains an entry for this variant (Variation ID: 2074348). This variant has not been reported in the literature in individuals affected with TSPEAR-related conditions. This variant is present in population databases (rs782367814, gnomAD 0.02%). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.27
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.078	T;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.86	D
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.51	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.57	T
Polyphen		1.0	D;D
Vest4		0.61
MVP		0.39
MPC		0.16
ClinPred		0.79	D
GERP RS		4.3
Varity_R		0.38
gMVP		0.61

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: rs782367814; hg19: chr21-45919770;