chr21-44533935-G-C

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_144991.3(TSPEAR):​c.304-12C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 1,604,374 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000013 (0 hom., cov: 28)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: TSPEAR NM_144991.3 intron
• Scores: Splicing: ADA: 0.001461
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).

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>G		intron	N/A	NP_659428.2
	TSPEAR	NM_001272037.2		c.100-12C>G		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>G		intron	N/A	ENSP00000321987.4
	TSPEAR	ENST00000397916.1	TSL:1	n.259-12C>G		intron	N/A
	TSPEAR	ENST00000642437.1		n.*249-12C>G		intron	N/A	ENSP00000496535.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151174 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.0000244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000418 AC: 1 AN: 238964 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000950

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000131 AC: 19 AN: 1453200 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 722276

African (AFR) AF: 0.00 AC: 0 AN: 33334

American (AMR) AF: 0.00 AC: 0 AN: 44508

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26022

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 85848

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 0.0000172 AC: 19 AN: 1106428

Other (OTH) AF: 0.00 AC: 0 AN: 60066

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151174 Hom.: 0 Cov.: 28 AF XY: 0.0000271 AC XY: 2 AN XY: 73736

African (AFR) AF: 0.0000244 AC: 1 AN: 41040

American (AMR) AF: 0.00 AC: 0 AN: 15190

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5032

South Asian (SAS) AF: 0.00 AC: 0 AN: 4750

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10546

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67850

Other (OTH) AF: 0.00 AC: 0 AN: 2078

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	13
DANN	Benign	0.48
PhyloP100		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0015
dbscSNV1_RF	Benign	0.066
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.32		Position offset: 19

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

Other links and lift over

dbSNP: rs192955018; hg19: chr21-45953818;