rs781928408

Variant names:

• chr21-44499873-C-T
• rs781928408
• NM_144991.3:c.1920G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_144991.3(TSPEAR):​c.1920G>A​(p.Trp640*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000275 in 1,453,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: TSPEAR NM_144991.3 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.41
• 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 Gene-Disease associations (from GenCC):

• ectodermal dysplasia 14, hair/tooth type with or without hypohidrosis

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive nonsyndromic hearing loss 98

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0448 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

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.1920G>A	p.Trp640*	stop_gained	Exon 12 of 12	NP_659428.2
	TSPEAR	NM_001272037.2		c.1716G>A	p.Trp572*	stop_gained	Exon 13 of 13	NP_001258966.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSPEAR	ENST00000323084.9	TSL:1 MANE Select	c.1920G>A	p.Trp640*	stop_gained	Exon 12 of 12	ENSP00000321987.4	Q8WU66-1
	TSPEAR	ENST00000943283.1		c.2046G>A	p.Trp682*	stop_gained	Exon 13 of 13	ENSP00000613342.1
	TSPEAR	ENST00000642437.1		n.*1865G>A		non_coding_transcript_exon	Exon 13 of 13	ENSP00000496535.1	A0A2R8YFK6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000432 AC: 1 AN: 231290 AF XY: 0.00000790

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000976

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1453716 Hom.: 0 Cov.: 31 AF XY: 0.00000277 AC XY: 2 AN XY: 722698

African (AFR) AF: 0.00 AC: 0 AN: 33146

American (AMR) AF: 0.00 AC: 0 AN: 44104

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25856

East Asian (EAS) AF: 0.00 AC: 0 AN: 39180

South Asian (SAS) AF: 0.00 AC: 0 AN: 84904

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5604

European-Non Finnish (NFE) AF: 0.00000361 AC: 4 AN: 1109282

Other (OTH) AF: 0.00 AC: 0 AN: 60032

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000827 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.86	D
PhyloP100		5.4
Vest4		0.27
GERP RS		4.3
Mutation Taster		=13/187	disease causing

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: rs781928408; hg19: chr21-45919756;