21-44533935-G-A

Variant names:

• chr21-44533935-G-A
• rs192955018
• NM_144991.3:c.304-12C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_144991.3(TSPEAR):​c.304-12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000946 in 1,604,490 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (2 hom., cov: 28)
  • Exomes 𝑓: 0.00084 (6 hom.)
• Consequence: TSPEAR NM_144991.3 intron
• Scores: Splicing: ADA: 0.00001879
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.283
• 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, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 21-44533935-G-A is Benign according to our data. Variant chr21-44533935-G-A is described in ClinVar as Benign. ClinVar VariationId is 504831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00197 (298/151292) while in subpopulation AFR AF = 0.00498 (205/41162). AF 95% confidence interval is 0.00442. There are 2 homozygotes in GnomAd4. There are 146 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSPEAR	NM_144991.3	MANE Select	c.304-12C>T		intron	N/A	NP_659428.2
	TSPEAR	NM_001272037.2		c.100-12C>T		intron	N/A	NP_001258966.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSPEAR	ENST00000323084.9	TSL:1 MANE Select	c.304-12C>T		intron	N/A	ENSP00000321987.4
	TSPEAR	ENST00000397916.1	TSL:1	n.259-12C>T		intron	N/A
	TSPEAR	ENST00000642437.1		n.*249-12C>T		intron	N/A	ENSP00000496535.1

Frequencies

GnomAD3 genomes AF: 0.00192 AC: 290 AN: 151174 Hom.: 1 Cov.: 28

Gnomad AFR AF: 0.00480

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000842

Gnomad FIN AF: 0.0000948

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000648

Gnomad OTH AF: 0.00577

GnomAD2 exomes AF: 0.00113 AC: 270 AN: 238964 AF XY: 0.00110

Gnomad AFR exome AF: 0.00518

Gnomad AMR exome AF: 0.000997

Gnomad ASJ exome AF: 0.000411

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000959

Gnomad OTH exome AF: 0.00238

GnomAD4 exome AF: 0.000840 AC: 1220 AN: 1453198 Hom.: 6 Cov.: 31 AF XY: 0.000836 AC XY: 604 AN XY: 722274

African (AFR) AF: 0.00615 AC: 205 AN: 33332

American (AMR) AF: 0.00108 AC: 48 AN: 44508

Ashkenazi Jewish (ASJ) AF: 0.000615 AC: 16 AN: 26022

East Asian (EAS) AF: 0.00 AC: 0 AN: 39484

South Asian (SAS) AF: 0.00129 AC: 111 AN: 85848

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51804

Middle Eastern (MID) AF: 0.0235 AC: 134 AN: 5706

European-Non Finnish (NFE) AF: 0.000523 AC: 579 AN: 1106428

Other (OTH) AF: 0.00211 AC: 127 AN: 60066

GnomAD4 genome AF: 0.00197 AC: 298 AN: 151292 Hom.: 2 Cov.: 28 AF XY: 0.00198 AC XY: 146 AN XY: 73864

African (AFR) AF: 0.00498 AC: 205 AN: 41162

American (AMR) AF: 0.00151 AC: 23 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5020

South Asian (SAS) AF: 0.000843 AC: 4 AN: 4746

European-Finnish (FIN) AF: 0.0000948 AC: 1 AN: 10546

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000649 AC: 44 AN: 67842

Other (OTH) AF: 0.00571 AC: 12 AN: 2100

Alfa AF: 0.000514 Hom.: 0

Bravo AF: 0.00224

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jan 25, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

304-12C>T in intron 2 of TSPEAR: This variant is not expected to have clinical s ignificance because it has been identified in 0.5% (21/4386) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs192955018).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.7
DANN	Benign	0.67
PhyloP100		0.28
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000019
dbscSNV1_RF	Benign	0.0
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: rs192955018; hg19: chr21-45953818;