chr21-44533935-G-A

Position:

• chr21-44533935-G-A

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.304-12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000946 in 1,604,490 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (2 hom., cov: 28)
  • Exomes 𝑓: 0.00084 (6 hom.)
• Consequence: TSPEAR NM_144991.3 intron
• Scores: Splicing: ADA: 0.00001879
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.283

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 21-44533935-G-A is Benign according to our data. Variant chr21-44533935-G-A is described in ClinVar as [Benign]. Clinvar id is 504831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00084 (1220/1453198) while in subpopulation MID AF= 0.0235 (134/5706). AF 95% confidence interval is 0.0202. There are 6 homozygotes in gnomad4_exome. There are 604 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSPEAR	NM_144991.3	c.304-12C>T		intron_variant		ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2	c.100-12C>T		intron_variant			NP_001258966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSPEAR	ENST00000323084.9	c.304-12C>T		intron_variant		1	NM_144991.3	ENSP00000321987.4
TSPEAR	ENST00000397916.1	n.259-12C>T		intron_variant		1
TSPEAR	ENST00000642437.1	n.*249-12C>T		intron_variant				ENSP00000496535.1

Frequencies

GnomAD3 genomes AF: 0.00192 AC: 290 AN: 151174 Hom.: 1 Cov.: 28

Gnomad AFR AF: 0.00480

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000842

Gnomad FIN AF: 0.0000948

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000648

Gnomad OTH AF: 0.00577

GnomAD3 exomes AF: 0.00113 AC: 270 AN: 238964 Hom.: 0 AF XY: 0.00110 AC XY: 144 AN XY: 130820

Gnomad AFR exome AF: 0.00518

Gnomad AMR exome AF: 0.000997

Gnomad ASJ exome AF: 0.000411

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00129

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000959

Gnomad OTH exome AF: 0.00238

GnomAD4 exome AF: 0.000840 AC: 1220 AN: 1453198 Hom.: 6 Cov.: 31 AF XY: 0.000836 AC XY: 604 AN XY: 722274

Gnomad4 AFR exome AF: 0.00615

Gnomad4 AMR exome AF: 0.00108

Gnomad4 ASJ exome AF: 0.000615

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00129

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000523

Gnomad4 OTH exome AF: 0.00211

GnomAD4 genome AF: 0.00197 AC: 298 AN: 151292 Hom.: 2 Cov.: 28 AF XY: 0.00198 AC XY: 146 AN XY: 73864

Gnomad4 AFR AF: 0.00498

Gnomad4 AMR AF: 0.00151

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000843

Gnomad4 FIN AF: 0.0000948

Gnomad4 NFE AF: 0.000649

Gnomad4 OTH AF: 0.00571

Alfa AF: 0.000514 Hom.: 0

Bravo AF: 0.00224

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 25, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2014

304-12C>T in intron 2 of TSPEAR: This variant is not expected to have clinical s ignificance because it has been identified in 0.5% (21/4386) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs192955018). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.7
DANN	Benign	0.67

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000019
dbscSNV1_RF	Benign	0.0
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: rs192955018; hg19: chr21-45953818;