rs35028190

Positions:

• chr21-44525765-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_144991.3(TSPEAR):​c.1224C>G​(p.His408Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0609 in 1,614,070 control chromosomes in the GnomAD database, including 3,432 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.047 (217 hom., cov: 33)
  • Exomes 𝑓: 0.062 (3215 hom.)
• Consequence: TSPEAR NM_144991.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.326

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]

TSPEAR-AS2 (HGNC:16428): (TSPEAR antisense RNA 2)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022302568).
• BP6: Variant 21-44525765-G-C is Benign according to our data. Variant chr21-44525765-G-C is described in ClinVar as [Benign]. Clinvar id is 227130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.068 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSPEAR	NM_144991.3	c.1224C>G	p.His408Gln	missense_variant	8/12	ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2	c.1020C>G	p.His340Gln	missense_variant	9/13		NP_001258966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSPEAR	ENST00000323084.9	c.1224C>G	p.His408Gln	missense_variant	8/12	1	NM_144991.3	ENSP00000321987	P1
TSPEAR	ENST00000397916.1	n.1179C>G		non_coding_transcript_exon_variant	8/11	1
TSPEAR-AS2	ENST00000465978.1	n.217-59G>C		intron_variant, non_coding_transcript_variant		5
TSPEAR	ENST00000642437.1	c.*1169C>G		3_prime_UTR_variant, NMD_transcript_variant	9/13			ENSP00000496535

Frequencies

GnomAD3 genomes AF: 0.0472 AC: 7182 AN: 152106 Hom.: 217 Cov.: 33

Gnomad AFR AF: 0.0123

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.0331

Gnomad ASJ AF: 0.0311

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0193

Gnomad FIN AF: 0.103

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0697

Gnomad OTH AF: 0.0417

GnomAD3 exomes AF: 0.0479 AC: 12045 AN: 251484 Hom.: 440 AF XY: 0.0483 AC XY: 6562 AN XY: 135914

Gnomad AFR exome AF: 0.0105

Gnomad AMR exome AF: 0.0234

Gnomad ASJ exome AF: 0.0286

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.0214

Gnomad FIN exome AF: 0.103

Gnomad NFE exome AF: 0.0666

Gnomad OTH exome AF: 0.0502

GnomAD4 exome AF: 0.0623 AC: 91140 AN: 1461846 Hom.: 3215 Cov.: 31 AF XY: 0.0613 AC XY: 44546 AN XY: 727224

Gnomad4 AFR exome AF: 0.00953

Gnomad4 AMR exome AF: 0.0252

Gnomad4 ASJ exome AF: 0.0293

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.0227

Gnomad4 FIN exome AF: 0.102

Gnomad4 NFE exome AF: 0.0706

Gnomad4 OTH exome AF: 0.0483

GnomAD4 genome AF: 0.0472 AC: 7182 AN: 152224 Hom.: 217 Cov.: 33 AF XY: 0.0465 AC XY: 3461 AN XY: 74428

Gnomad4 AFR AF: 0.0122

Gnomad4 AMR AF: 0.0331

Gnomad4 ASJ AF: 0.0311

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0199

Gnomad4 FIN AF: 0.103

Gnomad4 NFE AF: 0.0697

Gnomad4 OTH AF: 0.0412

Alfa AF: 0.0576 Hom.: 101

Bravo AF: 0.0398

TwinsUK AF: 0.0688 AC: 255

ALSPAC AF: 0.0758 AC: 292

ESP6500AA AF: 0.0134 AC: 59

ESP6500EA AF: 0.0647 AC: 556

ExAC AF: 0.0470 AC: 5703

Asia WGS AF: 0.00866 AC: 30 AN: 3478

EpiCase AF: 0.0625

EpiControl AF: 0.0613

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 26, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	His408Gln in exon 8 of TSPEAR: This variant is not expected to have clinical sig nificance because it has been identified in 6.5% (556/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs35028190). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	12
DANN	Benign	0.76
DEOGEN2	Benign	0.15	T;T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.53	.;T
MetaRNN	Benign	0.0022	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.0	.;N
REVEL	Benign	0.094
Sift	Benign	0.69	.;T
Sift4G	Benign	0.61	.;T
Polyphen		0.0030	B;B
Vest4		0.13
MutPred		0.27		Gain of catalytic residue at H408 (P = 0.0067);Gain of catalytic residue at H408 (P = 0.0067);
MPC		0.052
ClinPred		0.000023	T
GERP RS		1.6
Varity_R		0.064
gMVP		0.19

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: rs35028190; hg19: chr21-45945648;