rs200116408

Variant names:

• chr21-44533671-G-A
• rs200116408
• NM_144991.3:c.542+14C>T

Your query was ambiguous. Multiple possible variants found:

• chr21-44533671-G-A
• chr21-44533671-G-C
• chr21-44533671-G-T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000323084.9(TSPEAR):​c.542+14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00101 in 1,595,716 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00097 (2 hom.)
• Consequence: TSPEAR ENST00000323084.9 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.66
• 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 21-44533671-G-A is Benign according to our data. Variant chr21-44533671-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000323084.9. 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.542+14C>T		intron	N/A	NP_659428.2
	TSPEAR	NM_001272037.2		c.338+14C>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.542+14C>T		intron	N/A	ENSP00000321987.4
	TSPEAR	ENST00000397916.1	TSL:1	n.497+14C>T		intron	N/A
	TSPEAR	ENST00000642437.1		n.*487+14C>T		intron	N/A	ENSP00000496535.1

Frequencies

GnomAD3 genomes AF: 0.00135 AC: 205 AN: 152198 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000970

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000788 AC: 186 AN: 236136 AF XY: 0.000701

Gnomad AFR exome AF: 0.00330

Gnomad AMR exome AF: 0.000645

Gnomad ASJ exome AF: 0.000827

Gnomad EAS exome AF: 0.0000554

Gnomad FIN exome AF: 0.000109

Gnomad NFE exome AF: 0.000960

Gnomad OTH exome AF: 0.000511

GnomAD4 exome AF: 0.000969 AC: 1398 AN: 1443400 Hom.: 2 Cov.: 31 AF XY: 0.000909 AC XY: 651 AN XY: 716034

African (AFR) AF: 0.00205 AC: 68 AN: 33192

American (AMR) AF: 0.000676 AC: 30 AN: 44368

Ashkenazi Jewish (ASJ) AF: 0.000849 AC: 22 AN: 25910

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39346

South Asian (SAS) AF: 0.0000350 AC: 3 AN: 85682

European-Finnish (FIN) AF: 0.000143 AC: 7 AN: 49118

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5262

European-Non Finnish (NFE) AF: 0.00110 AC: 1215 AN: 1100986

Other (OTH) AF: 0.000873 AC: 52 AN: 59536

GnomAD4 genome AF: 0.00135 AC: 206 AN: 152316 Hom.: 0 Cov.: 30 AF XY: 0.00136 AC XY: 101 AN XY: 74478

African (AFR) AF: 0.00315 AC: 131 AN: 41568

American (AMR) AF: 0.000392 AC: 6 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000970 AC: 66 AN: 68034

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.000539 Hom.: 0

Bravo AF: 0.00138

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely 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	-0.91
CADD	Benign	0.69
DANN	Benign	0.36
PhyloP100		-1.7
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: rs200116408; hg19: chr21-45953554;