rs782453883

Variant names:

• chr21-44499800-G-A
• rs782453883
• NM_144991.3:c.1993C>T

Your query was ambiguous. Multiple possible variants found:

• chr21-44499800-G-A
• chr21-44499800-G-T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_144991.3(TSPEAR):​c.1993C>T​(p.Arg665Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000282 in 1,420,072 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R665Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: TSPEAR NM_144991.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.99
• 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: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.29725754).

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.1993C>T	p.Arg665Trp	missense	Exon 12 of 12	NP_659428.2
	TSPEAR	NM_001272037.2		c.1789C>T	p.Arg597Trp	missense	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.1993C>T	p.Arg665Trp	missense	Exon 12 of 12	ENSP00000321987.4	Q8WU66-1
	TSPEAR	ENST00000943283.1		c.2119C>T	p.Arg707Trp	missense	Exon 13 of 13	ENSP00000613342.1
	TSPEAR	ENST00000642437.1		n.*1938C>T		non_coding_transcript_exon	Exon 13 of 13	ENSP00000496535.1	A0A2R8YFK6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000164 AC: 3 AN: 182552 AF XY: 0.0000203

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: 0.0000395

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000282 AC: 40 AN: 1420072 Hom.: 0 Cov.: 31 AF XY: 0.0000299 AC XY: 21 AN XY: 702818

African (AFR) AF: 0.000248 AC: 8 AN: 32260

American (AMR) AF: 0.00 AC: 0 AN: 39318

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25306

East Asian (EAS) AF: 0.00 AC: 0 AN: 37130

South Asian (SAS) AF: 0.0000247 AC: 2 AN: 80846

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4918

European-Non Finnish (NFE) AF: 0.0000211 AC: 23 AN: 1092214

Other (OTH) AF: 0.000119 AC: 7 AN: 58714

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000168 AC: 2

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.087	T
Eigen	Benign	0.14
Eigen_PC	Benign	0.065
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		3.0
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.16
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.11
MutPred		0.59		Gain of sheet (P = 0.0036)
MVP		0.16
MPC		0.26
ClinPred		0.70	D
GERP RS		0.61
Varity_R		0.17
gMVP		0.70
Mutation Taster		=86/14	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: rs782453883; hg19: chr21-45919683;