rs425667

Variant names:

• chr21-44572248-T-C
• rs425667
• NM_144991.3:c.83-4243A>G

Your query was ambiguous. Multiple possible variants found:

• chr21-44572248-T-C
• chr21-44572248-T-G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_144991.3(TSPEAR):​c.83-4243A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.687 in 151,676 control chromosomes in the GnomAD database, including 36,898 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.69 (36898 hom., cov: 31)
• Consequence: TSPEAR NM_144991.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.178
• Publications: 5 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (Cadd=2.636).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.775 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSPEAR	NM_144991.3	c.83-4243A>G		intron_variant	Intron 1 of 11	ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2	c.-122-4243A>G		intron_variant	Intron 2 of 12		NP_001258966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSPEAR	ENST00000323084.9	c.83-4243A>G		intron_variant	Intron 1 of 11	1	NM_144991.3	ENSP00000321987.4
TSPEAR	ENST00000397916.1	n.37+1532A>G		intron_variant	Intron 1 of 10	1
TSPEAR	ENST00000642437.1	n.*28-4243A>G		intron_variant	Intron 2 of 12			ENSP00000496535.1

Frequencies

GnomAD3 genomes AF: 0.687 AC: 104087 AN: 151558 Hom.: 36877 Cov.: 31

Gnomad AFR AF: 0.577

Gnomad AMI AF: 0.778

Gnomad AMR AF: 0.607

Gnomad ASJ AF: 0.812

Gnomad EAS AF: 0.330

Gnomad SAS AF: 0.611

Gnomad FIN AF: 0.781

Gnomad MID AF: 0.750

Gnomad NFE AF: 0.781

Gnomad OTH AF: 0.714

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.687 AC: 104156 AN: 151676 Hom.: 36898 Cov.: 31 AF XY: 0.681 AC XY: 50463 AN XY: 74120

African (AFR) AF: 0.577 AC: 23844 AN: 41318

American (AMR) AF: 0.606 AC: 9247 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.812 AC: 2813 AN: 3464

East Asian (EAS) AF: 0.331 AC: 1695 AN: 5126

South Asian (SAS) AF: 0.612 AC: 2948 AN: 4818

European-Finnish (FIN) AF: 0.781 AC: 8211 AN: 10520

Middle Eastern (MID) AF: 0.759 AC: 223 AN: 294

European-Non Finnish (NFE) AF: 0.781 AC: 52975 AN: 67858

Other (OTH) AF: 0.710 AC: 1494 AN: 2104

Alfa AF: 0.738 Hom.: 77983

Bravo AF: 0.670

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
CADD	Benign	2.6
PhyloP100		-0.18

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs425667; hg19: -;