21-44509162-A-C

Variant names:

• chr21-44509162-A-C
• rs148385524
• NM_144991.3:c.1754+37T>G

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+37T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000697 in 1,593,028 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (3 hom.)
• Consequence: TSPEAR NM_144991.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.726
• 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 (BayesDel_noAF=-1.03).
• BP6: Variant 21-44509162-A-C is Benign according to our data. Variant chr21-44509162-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1207370.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 = 0.00375 (571/152240) while in subpopulation AFR AF = 0.013 (541/41532). AF 95% confidence interval is 0.0121. There are 6 homozygotes in GnomAd4. There are 263 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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+37T>G		intron	N/A	NP_659428.2
	TSPEAR	NM_001272037.2		c.1550+37T>G		intron	N/A	NP_001258966.1
	TSPEAR-AS1	NR_103707.1		n.1215-90A>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSPEAR	ENST00000323084.9	TSL:1 MANE Select	c.1754+37T>G		intron	N/A	ENSP00000321987.4	Q8WU66-1
	TSPEAR	ENST00000397916.1	TSL:1	n.1709+37T>G		intron	N/A
	TSPEAR	ENST00000943283.1		c.1754+37T>G		intron	N/A	ENSP00000613342.1

Frequencies

GnomAD3 genomes AF: 0.00376 AC: 572 AN: 152122 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0131

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.000946 AC: 231 AN: 244130 AF XY: 0.000697

Gnomad AFR exome AF: 0.0123

Gnomad AMR exome AF: 0.000587

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000908

Gnomad OTH exome AF: 0.000839

GnomAD4 exome AF: 0.000374 AC: 539 AN: 1440788 Hom.: 3 Cov.: 30 AF XY: 0.000320 AC XY: 229 AN XY: 714814

African (AFR) AF: 0.0119 AC: 396 AN: 33150

American (AMR) AF: 0.000588 AC: 26 AN: 44212

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25522

East Asian (EAS) AF: 0.00 AC: 0 AN: 39392

South Asian (SAS) AF: 0.0000472 AC: 4 AN: 84774

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52696

Middle Eastern (MID) AF: 0.00267 AC: 15 AN: 5624

European-Non Finnish (NFE) AF: 0.0000374 AC: 41 AN: 1095904

Other (OTH) AF: 0.000958 AC: 57 AN: 59514

GnomAD4 genome AF: 0.00375 AC: 571 AN: 152240 Hom.: 6 Cov.: 32 AF XY: 0.00353 AC XY: 263 AN XY: 74432

African (AFR) AF: 0.0130 AC: 541 AN: 41532

American (AMR) AF: 0.000980 AC: 15 AN: 15300

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68022

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.000829 Hom.: 0

Bravo AF: 0.00425

Asia WGS AF: 0.000289 AC: 1 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	-1.0
CADD	Benign	0.20
DANN	Benign	0.44
PhyloP100		-0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs148385524; hg19: chr21-45929045;