rs200116408

chr21-44533671-G-Achr21-44533671-G-Tchr21-44533671-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_144991.3(TSPEAR):c.542+14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00101 in 1,595,716 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00097 (2 hom.)
• Consequence: TSPEAR NM_144991.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.66

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 21-44533671-G-A is Benign according to our data. Variant chr21-44533671-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 227138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSPEAR	NM_144991.3	c.542+14C>T		intron_variant		ENST00000323084.9
TSPEAR	NM_001272037.2	c.338+14C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSPEAR	ENST00000323084.9	c.542+14C>T		intron_variant		1	NM_144991.3	P1
TSPEAR	ENST00000397916.1	n.497+14C>T		intron_variant, non_coding_transcript_variant		1
TSPEAR	ENST00000642437.1	c.*487+14C>T		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00135 AC: 205 AN: 152198 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000970

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000788 AC: 186 AN: 236136 Hom.: 1 AF XY: 0.000701 AC XY: 91 AN XY: 129836

Gnomad AFR exome AF: 0.00330

Gnomad AMR exome AF: 0.000645

Gnomad ASJ exome AF: 0.000827

Gnomad EAS exome AF: 0.0000554

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000109

Gnomad NFE exome AF: 0.000960

Gnomad OTH exome AF: 0.000511

GnomAD4 exome AF: 0.000969 AC: 1398 AN: 1443400 Hom.: 2 Cov.: 31 AF XY: 0.000909 AC XY: 651 AN XY: 716034

Gnomad4 AFR exome AF: 0.00205

Gnomad4 AMR exome AF: 0.000676

Gnomad4 ASJ exome AF: 0.000849

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.0000350

Gnomad4 FIN exome AF: 0.000143

Gnomad4 NFE exome AF: 0.00110

Gnomad4 OTH exome AF: 0.000873

GnomAD4 genome AF: 0.00135 AC: 206 AN: 152316 Hom.: 0 Cov.: 30 AF XY: 0.00136 AC XY: 101 AN XY: 74478

Gnomad4 AFR AF: 0.00315

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000970

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000539 Hom.: 0

Bravo AF: 0.00138

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 10, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2020	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 17, 2015

542+14C>T in intron 3 of TSPEAR: This variant is not expected to have clinical s ignificance because it is not located within the conserved splice consensus sequ ence and because it has been identified in 0.4% (29/7930) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSN P rs200116408). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.69
Dann	Benign	0.36

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: rs200116408; hg19: chr21-45953554;