rs75351275

chr21-44711464-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_144991.3(TSPEAR):c.51C>T(p.Gly17=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,611,134 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0071 (10 hom., cov: 32)
  • Exomes 𝑓: 0.00070 (18 hom.)
• Consequence: TSPEAR NM_144991.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.72

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 21-44711464-G-A is Benign according to our data. Variant chr21-44711464-G-A is described in ClinVar as [Benign]. Clinvar id is 227136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-44711464-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.72 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00715 (1089/152358) while in subpopulation AFR AF= 0.0248 (1031/41580). AF 95% confidence interval is 0.0235. There are 10 homozygotes in gnomad4. There are 492 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSPEAR	NM_144991.3	c.51C>T	p.Gly17=	synonymous_variant	1/12	ENST00000323084.9
TSPEAR	NM_001272037.2	c.-216C>T		5_prime_UTR_variant	1/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSPEAR	ENST00000323084.9	c.51C>T	p.Gly17=	synonymous_variant	1/12	1	NM_144991.3	P1
TSPEAR	ENST00000642437.1	c.51C>T	p.Gly17=	synonymous_variant, NMD_transcript_variant	1/13

Frequencies

GnomAD3 genomes AF: 0.00715 AC: 1088 AN: 152240 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0248

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00248

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00163 AC: 394 AN: 242384 Hom.: 5 AF XY: 0.00117 AC XY: 154 AN XY: 132074

Gnomad AFR exome AF: 0.0217

Gnomad AMR exome AF: 0.00115

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000200

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000137

Gnomad OTH exome AF: 0.00102

GnomAD4 exome AF: 0.000698 AC: 1018 AN: 1458776 Hom.: 18 Cov.: 30 AF XY: 0.000606 AC XY: 440 AN XY: 725522

Gnomad4 AFR exome AF: 0.0235

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000198

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000288

Gnomad4 OTH exome AF: 0.00186

GnomAD4 genome AF: 0.00715 AC: 1089 AN: 152358 Hom.: 10 Cov.: 32 AF XY: 0.00660 AC XY: 492 AN XY: 74520

Gnomad4 AFR AF: 0.0248

Gnomad4 AMR AF: 0.00248

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00373 Hom.: 2

Bravo AF: 0.00813

Asia WGS AF: 0.00231 AC: 10 AN: 3478

ClinVar

Significance: 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	GeneDx	Aug 20, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 22, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2014

Gly17Gly in exon 1 of TSPEAR: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 2.0% (89/4402) of Af rican American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs75351275). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	4.1
Dann	Benign	0.62

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: rs75351275; hg19: chr21-46131379;