rs117791519

Variant names:

• chr21-44529886-G-A
• rs117791519
• NM_144991.3:c.702C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_144991.3(TSPEAR):​c.702C>T​(p.Asn234Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00567 in 1,613,222 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0045 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0058 (27 hom.)
• Consequence: TSPEAR NM_144991.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.06
• Publications: 3 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, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

LOC124905038 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 21-44529886-G-A is Benign according to our data. Variant chr21-44529886-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227140.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.07 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0045 (686/152340) while in subpopulation NFE AF = 0.00817 (556/68022). AF 95% confidence interval is 0.00761. There are 5 homozygotes in GnomAd4. There are 348 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

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.702C>T	p.Asn234Asn	synonymous	Exon 5 of 12	NP_659428.2
	TSPEAR	NM_001272037.2		c.498C>T	p.Asn166Asn	synonymous	Exon 6 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.702C>T	p.Asn234Asn	synonymous	Exon 5 of 12	ENSP00000321987.4
	TSPEAR	ENST00000397916.1	TSL:1	n.657C>T		non_coding_transcript_exon	Exon 5 of 11
	TSPEAR	ENST00000943283.1		c.702C>T	p.Asn234Asn	synonymous	Exon 5 of 13	ENSP00000613342.1

Frequencies

GnomAD3 genomes AF: 0.00450 AC: 685 AN: 152222 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00817

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00445 AC: 1113 AN: 249956 AF XY: 0.00433

Gnomad AFR exome AF: 0.00130

Gnomad AMR exome AF: 0.00156

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00242

Gnomad NFE exome AF: 0.00842

Gnomad OTH exome AF: 0.00410

GnomAD4 exome AF: 0.00579 AC: 8456 AN: 1460882 Hom.: 27 Cov.: 31 AF XY: 0.00550 AC XY: 3999 AN XY: 726792

African (AFR) AF: 0.000896 AC: 30 AN: 33468

American (AMR) AF: 0.00130 AC: 58 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26102

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39696

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86254

European-Finnish (FIN) AF: 0.00306 AC: 161 AN: 52700

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5760

European-Non Finnish (NFE) AF: 0.00713 AC: 7930 AN: 1111840

Other (OTH) AF: 0.00421 AC: 254 AN: 60374

GnomAD4 genome AF: 0.00450 AC: 686 AN: 152340 Hom.: 5 Cov.: 33 AF XY: 0.00467 AC XY: 348 AN XY: 74498

African (AFR) AF: 0.00113 AC: 47 AN: 41574

American (AMR) AF: 0.00340 AC: 52 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00198 AC: 21 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00817 AC: 556 AN: 68022

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00676 Hom.: 4

Bravo AF: 0.00409

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00660

EpiControl AF: 0.00623

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	not specified (1)
-	-	1	TSPEAR-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.8
DANN	Benign	0.91
PhyloP100		-1.1
Mutation Taster		=100/0	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: rs117791519; hg19: chr21-45949769;