rs199699551

chr21-44528597-C-Gchr21-44528597-C-Tchr21-44528597-C-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_144991.3(TSPEAR):c.791-14G>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000607 in 1,612,610 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00063 (0 hom.)
• Consequence: TSPEAR NM_144991.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.887

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]

LOC124905038 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 21-44528597-C-G is Benign according to our data. Variant chr21-44528597-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 229381.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSPEAR	NM_144991.3	c.791-14G>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000323084.9
LOC124905038	XR_007067905.1	n.1089C>G		non_coding_transcript_exon_variant	1/2
TSPEAR	NM_001272037.2	c.587-14G>C		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSPEAR	ENST00000323084.9	c.791-14G>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_144991.3	P1
TSPEAR	ENST00000397916.1	n.746-14G>C		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		1
TSPEAR	ENST00000642437.1	c.*736-14G>C		splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 152182 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000706

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000389 AC: 97 AN: 249536 Hom.: 0 AF XY: 0.000422 AC XY: 57 AN XY: 135032

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000509

Gnomad NFE exome AF: 0.000717

Gnomad OTH exome AF: 0.000494

GnomAD4 exome AF: 0.000629 AC: 918 AN: 1460310 Hom.: 0 Cov.: 31 AF XY: 0.000625 AC XY: 454 AN XY: 726472

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000451

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000582

Gnomad4 NFE exome AF: 0.000783

Gnomad4 OTH exome AF: 0.000216

GnomAD4 genome AF: 0.000401 AC: 61 AN: 152300 Hom.: 0 Cov.: 33 AF XY: 0.000430 AC XY: 32 AN XY: 74472

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.000706

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000179 Hom.: 0

Bravo AF: 0.000359

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 11, 2017

The c.791-14G>C variant in TSPEAR has been previously reported by our laboratory in 1 individual with hearing loss, but a variant affecting the other copy of th e gene was not identified. This variant has been identified in 83/126028 Europea n chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadins titute.org; dbSNP rs199699551); however, this frequency is not high enough to ru le out a pathogenic role. This variant is located in the 3' splice region. Compu tational tools do not suggest an impact to splicing. However, this information i s not predictive enough to rule out pathogenicity. In summary, the clinical sig nificance of the c.791-14G>C variant is uncertain. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Nov 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	7.3
Dann	Benign	0.69

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: rs199699551; hg19: chr21-45948480;