21-44499798-C-A

Variant names:

• chr21-44499798-C-A
• NM_144991.3:c.1995G>T
• TSPEAR p.Arg665Arg

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_144991.3(TSPEAR):​c.1995G>T​(p.Arg665Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R665R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TSPEAR NM_144991.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.557
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP7: Synonymous conserved (PhyloP=0.557 with no splicing effect.

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.1995G>T	p.Arg665Arg	synonymous	Exon 12 of 12	NP_659428.2
	TSPEAR	NM_001272037.2		c.1791G>T	p.Arg597Arg	synonymous	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.1995G>T	p.Arg665Arg	synonymous	Exon 12 of 12	ENSP00000321987.4	Q8WU66-1
	TSPEAR	ENST00000943283.1		c.2121G>T	p.Arg707Arg	synonymous	Exon 13 of 13	ENSP00000613342.1
	TSPEAR	ENST00000642437.1		n.*1940G>T		non_coding_transcript_exon	Exon 13 of 13	ENSP00000496535.1	A0A2R8YFK6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1419320 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 702272

African (AFR) AF: 0.00 AC: 0 AN: 32258

American (AMR) AF: 0.00 AC: 0 AN: 39264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25296

East Asian (EAS) AF: 0.00 AC: 0 AN: 37110

South Asian (SAS) AF: 0.00 AC: 0 AN: 80764

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49290

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4874

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1091778

Other (OTH) AF: 0.00 AC: 0 AN: 58686

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	10
DANN	Benign	0.88
PhyloP100		0.56

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr21-45919681;