NM_144991.3:c.83-2558T>C

Variant names:

• chr21-44570563-A-G
• rs233275
• NM_144991.3:c.83-2558T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_144991.3(TSPEAR):​c.83-2558T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.429 in 152,064 control chromosomes in the GnomAD database, including 15,282 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.43 (15282 hom., cov: 32)
• Consequence: TSPEAR NM_144991.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.822
• Publications: 6 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.527 is higher than 0.05.

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.83-2558T>C		intron	N/A	NP_659428.2
	TSPEAR	NM_001272037.2		c.-122-2558T>C		intron	N/A	NP_001258966.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSPEAR	ENST00000323084.9	TSL:1 MANE Select	c.83-2558T>C		intron	N/A	ENSP00000321987.4	Q8WU66-1
	TSPEAR	ENST00000397916.1	TSL:1	n.38-2558T>C		intron	N/A
	TSPEAR	ENST00000943283.1		c.83-2558T>C		intron	N/A	ENSP00000613342.1

Frequencies

GnomAD3 genomes AF: 0.429 AC: 65255 AN: 151946 Hom.: 15286 Cov.: 32

Gnomad AFR AF: 0.281

Gnomad AMI AF: 0.561

Gnomad AMR AF: 0.353

Gnomad ASJ AF: 0.492

Gnomad EAS AF: 0.135

Gnomad SAS AF: 0.468

Gnomad FIN AF: 0.548

Gnomad MID AF: 0.522

Gnomad NFE AF: 0.532

Gnomad OTH AF: 0.465

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.429 AC: 65249 AN: 152064 Hom.: 15282 Cov.: 32 AF XY: 0.427 AC XY: 31713 AN XY: 74322

African (AFR) AF: 0.281 AC: 11663 AN: 41482

American (AMR) AF: 0.352 AC: 5386 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.492 AC: 1708 AN: 3470

East Asian (EAS) AF: 0.135 AC: 698 AN: 5184

South Asian (SAS) AF: 0.468 AC: 2253 AN: 4816

European-Finnish (FIN) AF: 0.548 AC: 5782 AN: 10554

Middle Eastern (MID) AF: 0.520 AC: 153 AN: 294

European-Non Finnish (NFE) AF: 0.532 AC: 36127 AN: 67958

Other (OTH) AF: 0.460 AC: 970 AN: 2110

Alfa AF: 0.485 Hom.: 18302

Bravo AF: 0.408

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	2.9
PhyloP100		0.82

Splicing

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

dbSNP: rs233275;

hg19: chr21-45990446;