chr21-44533693-C-T

Variant names:

• chr21-44533693-C-T
• rs148713881
• NM_144991.3:c.534G>A

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.534G>A​(p.Pro178Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00148 in 1,607,120 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0081 (17 hom., cov: 30)
  • Exomes 𝑓: 0.00079 (11 hom.)
• Consequence: TSPEAR NM_144991.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.316
• 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 21-44533693-C-T is Benign according to our data. Variant chr21-44533693-C-T is described in ClinVar as Benign. ClinVar VariationId is 227137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.316 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00813 (1238/152318) while in subpopulation AFR AF = 0.0287 (1195/41570). AF 95% confidence interval is 0.0274. There are 17 homozygotes in GnomAd4. There are 573 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 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.534G>A	p.Pro178Pro	synonymous	Exon 3 of 12	NP_659428.2
	TSPEAR	NM_001272037.2		c.330G>A	p.Pro110Pro	synonymous	Exon 4 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.534G>A	p.Pro178Pro	synonymous	Exon 3 of 12	ENSP00000321987.4	Q8WU66-1
	TSPEAR	ENST00000397916.1	TSL:1	n.489G>A		non_coding_transcript_exon	Exon 3 of 11
	TSPEAR	ENST00000943283.1		c.534G>A	p.Pro178Pro	synonymous	Exon 3 of 13	ENSP00000613342.1

Frequencies

GnomAD3 genomes AF: 0.00813 AC: 1238 AN: 152200 Hom.: 17 Cov.: 30

Gnomad AFR AF: 0.0288

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00203 AC: 488 AN: 240730 AF XY: 0.00153

Gnomad AFR exome AF: 0.0280

Gnomad AMR exome AF: 0.00105

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.000110

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.00117

GnomAD4 exome AF: 0.000788 AC: 1147 AN: 1454802 Hom.: 11 Cov.: 32 AF XY: 0.000688 AC XY: 497 AN XY: 722880

African (AFR) AF: 0.0272 AC: 907 AN: 33390

American (AMR) AF: 0.00126 AC: 56 AN: 44562

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26042

East Asian (EAS) AF: 0.0000759 AC: 3 AN: 39526

South Asian (SAS) AF: 0.0000581 AC: 5 AN: 86048

European-Finnish (FIN) AF: 0.0000196 AC: 1 AN: 51070

Middle Eastern (MID) AF: 0.000892 AC: 5 AN: 5604

European-Non Finnish (NFE) AF: 0.0000586 AC: 65 AN: 1108484

Other (OTH) AF: 0.00175 AC: 105 AN: 60076

GnomAD4 genome AF: 0.00813 AC: 1238 AN: 152318 Hom.: 17 Cov.: 30 AF XY: 0.00769 AC XY: 573 AN XY: 74466

African (AFR) AF: 0.0287 AC: 1195 AN: 41570

American (AMR) AF: 0.00176 AC: 27 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68026

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.00447 Hom.: 1

Bravo AF: 0.00902

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	7.0
DANN	Benign	0.60
PhyloP100		-0.32
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: rs148713881; hg19: chr21-45953576; COSMIC: COSV59969913;