21-44508907-C-T

Position:

• chr21-44508907-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_144991.3(TSPEAR):​c.1754+292G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000893 in 1,489,672 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0042 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00051 (8 hom.)
• Consequence: TSPEAR NM_144991.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.134

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-AS1 (HGNC:1271): (TSPEAR antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 21-44508907-C-T is Benign according to our data. Variant chr21-44508907-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1187115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00423 (645/152366) while in subpopulation AFR AF= 0.0143 (596/41584). AF 95% confidence interval is 0.0134. There are 7 homozygotes in gnomad4. There are 278 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSPEAR	NM_144991.3	c.1754+292G>A		intron_variant		ENST00000323084.9	NP_659428.2
TSPEAR-AS1	NR_103707.1	n.1192C>T		non_coding_transcript_exon_variant	4/7
TSPEAR	NM_001272037.2	c.1550+292G>A		intron_variant			NP_001258966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSPEAR	ENST00000323084.9	c.1754+292G>A		intron_variant		1	NM_144991.3	ENSP00000321987	P1
TSPEAR	ENST00000397916.1	n.1714G>A		non_coding_transcript_exon_variant	11/11	1
TSPEAR-AS1	ENST00000451035.2	n.747C>T		non_coding_transcript_exon_variant	3/6	5
TSPEAR	ENST00000642437.1	c.*1699+292G>A		intron_variant, NMD_transcript_variant				ENSP00000496535

Frequencies

GnomAD3 genomes AF: 0.00422 AC: 642 AN: 152248 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0143

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00104 AC: 234 AN: 225720 Hom.: 2 AF XY: 0.000878 AC XY: 109 AN XY: 124096

Gnomad AFR exome AF: 0.0139

Gnomad AMR exome AF: 0.000787

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000710

Gnomad SAS exome AF: 0.000284

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000302

Gnomad OTH exome AF: 0.00176

GnomAD4 exome AF: 0.000513 AC: 686 AN: 1337306 Hom.: 8 Cov.: 31 AF XY: 0.000477 AC XY: 316 AN XY: 662310

Gnomad4 AFR exome AF: 0.0164

Gnomad4 AMR exome AF: 0.000800

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000457

Gnomad4 SAS exome AF: 0.000290

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000454

Gnomad4 OTH exome AF: 0.00111

GnomAD4 genome AF: 0.00423 AC: 645 AN: 152366 Hom.: 7 Cov.: 32 AF XY: 0.00373 AC XY: 278 AN XY: 74504

Gnomad4 AFR AF: 0.0143

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00181 Hom.: 0

Bravo AF: 0.00465

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 31, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	4.2
DANN	Benign	0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs144039352; hg19: chr21-45928790;