rs782790512

Variant names:

• chr21-44504850-C-G
• rs782790512
• NM_144991.3:c.1786G>C

Your query was ambiguous. Multiple possible variants found:

• chr21-44504850-C-G
• chr21-44504850-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_144991.3(TSPEAR):​c.1786G>C​(p.Glu596Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E596D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 30)
• Consequence: TSPEAR NM_144991.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.29
• Publications: 4 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSPEAR	NM_144991.3	c.1786G>C	p.Glu596Gln	missense_variant	Exon 11 of 12	ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2	c.1582G>C	p.Glu528Gln	missense_variant	Exon 12 of 13		NP_001258966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSPEAR	ENST00000323084.9	c.1786G>C	p.Glu596Gln	missense_variant	Exon 11 of 12	1	NM_144991.3	ENSP00000321987.4
TSPEAR	ENST00000642437.1	n.*1731G>C		non_coding_transcript_exon_variant	Exon 12 of 13			ENSP00000496535.1
TSPEAR	ENST00000642437.1	n.*1731G>C		3_prime_UTR_variant	Exon 12 of 13			ENSP00000496535.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.0026	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.90	.;D
M_CAP	Uncertain	0.086	D
MetaRNN	Uncertain	0.57	D;D
MetaSVM	Uncertain	0.042	D
MutationAssessor	Benign	1.5	L;L
PhyloP100		4.3
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.0	.;N
REVEL	Uncertain	0.41
Sift	Benign	0.23	.;T
Sift4G	Uncertain	0.034	.;D
Polyphen		0.99	D;D
Vest4		0.40
MutPred		0.46		Gain of catalytic residue at E596 (P = 0.121);Gain of catalytic residue at E596 (P = 0.121);
MVP		0.70
MPC		0.063
ClinPred		0.82	D
GERP RS		4.7
Varity_R		0.19
gMVP		0.27
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs782790512; hg19: chr21-45924733;