rs151001222

chr21-44567918-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_144991.3(TSPEAR):c.170G>A(p.Arg57Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000401 in 1,605,430 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R57W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (6 hom.)
• Consequence: TSPEAR NM_144991.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 1.81

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015238225).
• BP6: Variant 21-44567918-C-T is Benign according to our data. Variant chr21-44567918-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 227132.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Likely_benign=3, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSPEAR	NM_144991.3	c.170G>A	p.Arg57Gln	missense_variant	2/12	ENST00000323084.9
TSPEAR	NM_001272037.2	c.-35G>A		5_prime_UTR_variant	3/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSPEAR	ENST00000323084.9	c.170G>A	p.Arg57Gln	missense_variant	2/12	1	NM_144991.3	P1
TSPEAR	ENST00000397916.1	n.125G>A		non_coding_transcript_exon_variant	2/11	1
TSPEAR	ENST00000642437.1	c.*115G>A		3_prime_UTR_variant, NMD_transcript_variant	3/13

Frequencies

GnomAD3 genomes AF: 0.00191 AC: 291 AN: 152114 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00642

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.000545 AC: 134 AN: 245710 Hom.: 1 AF XY: 0.000444 AC XY: 59 AN XY: 132896

Gnomad AFR exome AF: 0.00644

Gnomad AMR exome AF: 0.000395

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000107

Gnomad OTH exome AF: 0.000506

GnomAD4 exome AF: 0.000242 AC: 351 AN: 1453198 Hom.: 6 Cov.: 30 AF XY: 0.000237 AC XY: 171 AN XY: 722466

Gnomad4 AFR exome AF: 0.00669

Gnomad4 AMR exome AF: 0.000433

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000507

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000596

Gnomad4 OTH exome AF: 0.000550

GnomAD4 genome AF: 0.00192 AC: 292 AN: 152232 Hom.: 1 Cov.: 32 AF XY: 0.00191 AC XY: 142 AN XY: 74456

Gnomad4 AFR AF: 0.00643

Gnomad4 AMR AF: 0.000785

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.000479 Hom.: 0

Bravo AF: 0.00220

ESP6500AA AF: 0.00590 AC: 26

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000733 AC: 89

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 22, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 28, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 15, 2024	- -

TSPEAR-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 01, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2014

Arg57Gln in exon 2 of TSPEAR: This variant is not expected to have clinical sign ificance because it has been identified in 0.6% (26/4406) of African American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS; dbSNP rs151001222). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Benign	0.055	T;T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.34	N
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.015	T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.8	M;M
MutationTaster	Benign	1.0	D;N
PrimateAI	Benign	0.32	T
Sift4G	Uncertain	0.015	D;D
Polyphen		0.98	D;D
Vest4		0.26
MVP		0.040
MPC		0.056
ClinPred		0.016	T
GERP RS		2.8
Varity_R		0.072
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

LitVar

Other links and lift over

dbSNP: rs151001222; hg19: chr21-45987802; COSMIC: COSV59959974;