21-44567817-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6_Moderate

The NM_144991.3(TSPEAR):c.271G>A(p.Val91Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000332 in 1,594,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

TSPEAR
NM_144991.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.0660

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07272011).

BP6

Variant 21-44567817-C-T is Benign according to our data. Variant chr21-44567817-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 505156.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSPEAR	NM_144991.3 link	c.271G>A	p.Val91Ile	missense_variant	Exon 2 of 12	ENST00000323084.9	NP_659428.2	Q8WU66-1
TSPEAR	NM_001272037.2 link	c.67G>A	p.Val23Ile	missense_variant	Exon 3 of 13		NP_001258966.1	Q8WU66

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TSPEAR	ENST00000323084.9 link	c.271G>A	p.Val91Ile	missense_variant	Exon 2 of 12	1	NM_144991.3	ENSP00000321987.4	Q8WU66-1
TSPEAR	ENST00000397916.1 link	n.226G>A		non_coding_transcript_exon_variant	Exon 2 of 11	1
TSPEAR	ENST00000642437.1 link	n.*216G>A		non_coding_transcript_exon_variant	Exon 3 of 13			ENSP00000496535.1	A0A2R8YFK6
TSPEAR	ENST00000642437.1 link	n.*216G>A		3_prime_UTR_variant	Exon 3 of 13			ENSP00000496535.1	A0A2R8YFK6

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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

GnomAD3 exomes

AF:

0.00000833

AC:

AN:

239990

Hom.:

AF XY:

0.00

AC XY:

AN XY:

129802

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000631

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000354

AC:

AN:

1442442

Hom.:

Cov.:

AF XY:

0.0000210

AC XY:

AN XY:

715928

show subpopulations

Gnomad4 AFR exome

AF:

0.0000305

Gnomad4 AMR exome

AF:

0.0000477

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000427

Gnomad4 OTH exome

AF:

0.0000168

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Jun 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Val91Ile in exon 2 of TSPEAR: This variant is not expected to have clinical si gnificance due to a lack of conservation across species, including mammals. Of n ote, >5 mammals have a isoleucine (Ile) at this position despite high nearby ami no acid conservation. In addition, computational prediction tools do not suggest a high likelihood of impact to the protein. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.60

CADD

Benign

7.8

DANN

Benign

0.96

DEOGEN2

Benign

0.043

T;T

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.69

.;T

M_CAP

Benign

0.0013

MetaRNN

Benign

0.073

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

L;L

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.44

.;N

REVEL

Benign

0.033

Sift

Benign

0.097

.;T

Sift4G

Benign

0.18

T;T

Polyphen

0.10

B;B

Vest4

0.13

MutPred

0.41

Loss of sheet (P = 0.1907);Loss of sheet (P = 0.1907);

MVP

0.030

MPC

0.044

ClinPred

0.026

GERP RS

1.8

Varity_R

0.032

gMVP

0.26

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over