dbSNP rs754668171: THEMIS:p.Ala631Glu (chr6-127719690-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001010923.3(THEMIS):c.1892C>A(p.Ala631Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000041 in 1,610,374 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

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

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

THEMIS
NM_001010923.3 missense, splice_region

Scores

Splicing: ADA: 0.0004725

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.137

Publications

0 publications found

Variant links:

Genes affected

THEMIS (HGNC:21569): (thymocyte selection associated) This gene encodes a protein that plays a regulatory role in both positive and negative T-cell selection during late thymocyte development. The protein functions through T-cell antigen receptor signaling, and is necessary for proper lineage commitment and maturation of T-cells. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

THEMIS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07240683).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THEMIS	NM_001010923.3 link	c.1892C>A	p.Ala631Glu	missense_variant, splice_region_variant	Exon 5 of 6	ENST00000368248.5	NP_001010923.1	Q8N1K5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THEMIS	ENST00000368248.5 link	c.1892C>A	p.Ala631Glu	missense_variant, splice_region_variant	Exon 5 of 6	1	NM_001010923.3	ENSP00000357231.2		Q8N1K5-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151858

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.00000402

AC:

AN:

248836

AF XY:

0.00000743

show subpopulations

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:

0.00000886

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000439

AC:

AN:

1458516

Hom.:

Cov.:

AF XY:

0.0000482

AC XY:

AN XY:

725578

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33192

American (AMR)

AF:

0.00

AC:

AN:

44286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26000

East Asian (EAS)

AF:

0.00

AC:

AN:

39622

South Asian (SAS)

AF:

0.00

AC:

AN:

85832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53338

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.0000549

AC:

AN:

1110280

Other (OTH)

AF:

0.0000498

AC:

AN:

60226

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151858

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74156

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41370

American (AMR)

AF:

0.00

AC:

AN:

15230

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5148

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67902

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000534

Hom.:

ExAC

AF:

0.00000824

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0000547

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 12, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2009C>A (p.A670E) alteration is located in exon 6 (coding exon 6) of the THEMIS gene. This alteration results from a C to A substitution at nucleotide position 2009, causing the alanine (A) at amino acid position 670 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.45

CADD

Benign

4.1

(source)

DANN

Benign

0.68

DEOGEN2

Benign

0.063

T;T;.;T;.

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.056

LIST_S2

Benign

0.46

.;T;T;T;T

M_CAP

Benign

0.0077

MetaRNN

Benign

0.072

T;T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.55

N;N;.;.;.

PhyloP100

0.14

PrimateAI

Benign

0.32

PROVEAN

Benign

0.030

.;N;N;.;.

REVEL

Benign

0.19

Sift

Benign

0.033

.;D;D;.;.

Sift4G

Uncertain

0.057

T;T;T;T;T

Polyphen

0.0040

B;B;.;.;.

Vest4

0.12

MVP

0.31

ClinPred

0.086

GERP RS

1.2

Varity_R

0.090

gMVP

0.13

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00047

dbscSNV1_RF

Benign

0.11

SpliceAI score (max)

0.11

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over