21-44508907-C-T

Variant names:

• chr21-44508907-C-T
• rs144039352
• NM_144991.3:c.1754+292G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 0 publications found

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.014).
• 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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144991.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSPEAR	NM_144991.3	MANE Select	c.1754+292G>A		intron	N/A	NP_659428.2
	TSPEAR	NM_001272037.2		c.1550+292G>A		intron	N/A	NP_001258966.1
	TSPEAR-AS1	NR_103707.1		n.1192C>T		non_coding_transcript_exon	Exon 4 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSPEAR	ENST00000323084.9	TSL:1 MANE Select	c.1754+292G>A		intron	N/A	ENSP00000321987.4	Q8WU66-1
	TSPEAR	ENST00000397916.1	TSL:1	n.1714G>A		non_coding_transcript_exon	Exon 11 of 11
	TSPEAR	ENST00000943283.1		c.1754+292G>A		intron	N/A	ENSP00000613342.1

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

GnomAD2 exomes AF: 0.00104 AC: 234 AN: 225720 AF XY: 0.000878

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 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

African (AFR) AF: 0.0164 AC: 503 AN: 30696

American (AMR) AF: 0.000800 AC: 32 AN: 40024

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22316

East Asian (EAS) AF: 0.000457 AC: 13 AN: 28476

South Asian (SAS) AF: 0.000290 AC: 24 AN: 82634

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40582

Middle Eastern (MID) AF: 0.00154 AC: 8 AN: 5210

European-Non Finnish (NFE) AF: 0.0000454 AC: 47 AN: 1034414

Other (OTH) AF: 0.00111 AC: 59 AN: 52954

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

African (AFR) AF: 0.0143 AC: 596 AN: 41584

American (AMR) AF: 0.00229 AC: 35 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68040

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

Alfa AF: 0.00339 Hom.: 1

Bravo AF: 0.00465

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	4.2
DANN	Benign	0.89
PhyloP100		-0.13
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs144039352; hg19: chr21-45928790;