rs138480801

Variant names:

• chr21-44499878-C-T
• rs138480801
• NM_144991.3:c.1915G>A

Your query was ambiguous. Multiple possible variants found:

• chr21-44499878-C-T
• chr21-44499878-C-A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PM1 BP4_Strong BS1 BS2

The NM_144991.3(TSPEAR):​c.1915G>A​(p.Asp639Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00379 in 1,606,932 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0039 (18 hom.)
• Consequence: TSPEAR NM_144991.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:8 B:6
• Conservation: PhyloP100: 7.10
• Publications: 9 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: Benign. The variant received -10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_144991.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.012871683).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00228 (348/152346) while in subpopulation NFE AF = 0.00363 (247/68030). AF 95% confidence interval is 0.00326. There are 1 homozygotes in GnomAd4. There are 153 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 18 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.1915G>A	p.Asp639Asn	missense	Exon 12 of 12	NP_659428.2
	TSPEAR	NM_001272037.2		c.1711G>A	p.Asp571Asn	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.1915G>A	p.Asp639Asn	missense	Exon 12 of 12	ENSP00000321987.4	Q8WU66-1
	TSPEAR	ENST00000943283.1		c.2041G>A	p.Asp681Asn	missense	Exon 13 of 13	ENSP00000613342.1
	TSPEAR	ENST00000642437.1		n.*1860G>A		non_coding_transcript_exon	Exon 13 of 13	ENSP00000496535.1	A0A2R8YFK6

Frequencies

GnomAD3 genomes AF: 0.00229 AC: 348 AN: 152228 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00235

Gnomad ASJ AF: 0.00662

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00363

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00229 AC: 533 AN: 232456 AF XY: 0.00231

Gnomad AFR exome AF: 0.000698

Gnomad AMR exome AF: 0.00214

Gnomad ASJ exome AF: 0.00532

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000608

Gnomad NFE exome AF: 0.00360

Gnomad OTH exome AF: 0.00299

GnomAD4 exome AF: 0.00394 AC: 5738 AN: 1454586 Hom.: 18 Cov.: 31 AF XY: 0.00379 AC XY: 2743 AN XY: 723268

African (AFR) AF: 0.000633 AC: 21 AN: 33150

American (AMR) AF: 0.00244 AC: 108 AN: 44190

Ashkenazi Jewish (ASJ) AF: 0.00483 AC: 125 AN: 25888

East Asian (EAS) AF: 0.00 AC: 0 AN: 39256

South Asian (SAS) AF: 0.0000940 AC: 8 AN: 85146

European-Finnish (FIN) AF: 0.000968 AC: 50 AN: 51666

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5610

European-Non Finnish (NFE) AF: 0.00473 AC: 5254 AN: 1109620

Other (OTH) AF: 0.00286 AC: 172 AN: 60060

GnomAD4 genome AF: 0.00228 AC: 348 AN: 152346 Hom.: 1 Cov.: 33 AF XY: 0.00205 AC XY: 153 AN XY: 74496

African (AFR) AF: 0.000577 AC: 24 AN: 41570

American (AMR) AF: 0.00235 AC: 36 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00662 AC: 23 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00132 AC: 14 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00363 AC: 247 AN: 68030

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

Alfa AF: 0.00316 Hom.: 2

Bravo AF: 0.00239

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000912 AC: 4

ESP6500EA AF: 0.00291 AC: 25

ExAC AF: 0.00217 AC: 262

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	2	3	not provided (7)
3	1	-	Ectodermal dysplasia 14, hair/tooth type with or without hypohidrosis (4)
1	2	-	Tooth agenesis, selective, 10 (3)
-	1	1	not specified (2)
-	1	-	Autosomal recessive nonsyndromic hearing loss 98 (1)
-	-	1	Autosomal recessive nonsyndromic hearing loss 98;C4748560:Ectodermal dysplasia 14, hair/tooth type with or without hypohidrosis;C5774277:Tooth agenesis, selective, 10 (1)
-	1	-	Inborn genetic diseases (1)
-	-	1	TSPEAR-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.46
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.31	T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.095	D
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.1
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.28
Sift	Uncertain	0.025	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.64
MVP		0.30
MPC		0.33
ClinPred		0.022	T
GERP RS		4.3
Varity_R		0.42
gMVP		0.66
Mutation Taster		=74/26	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: rs138480801; hg19: chr21-45919761; COSMIC: COSV107388839; COSMIC: COSV107388839;