Genetic Variant THEMIS:p.Arg587His (chr6-127719822-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001010923.3(THEMIS):c.1760G>A(p.Arg587His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000478 in 1,611,004 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 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000046 ( 0 hom. )

Consequence

THEMIS
NM_001010923.3 missense, splice_region

Scores

Splicing: ADA: 0.0007014

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.523

Publications

1 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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07817599).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001010923.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
THEMIS	NM_001010923.3	MANE Select	c.1760G>A	p.Arg587His	missense splice_region	Exon 5 of 6	NP_001010923.1	Q8N1K5-1
THEMIS	NM_001164685.2		c.1877G>A	p.Arg626His	missense splice_region	Exon 6 of 7	NP_001158157.1	Q8N1K5-4
THEMIS	NM_001394520.1		c.1682G>A	p.Arg561His	missense splice_region	Exon 6 of 7	NP_001381449.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
THEMIS	ENST00000368248.5	TSL:1 MANE Select	c.1760G>A	p.Arg587His	missense splice_region	Exon 5 of 6	ENSP00000357231.2	Q8N1K5-1
THEMIS	ENST00000630369.2	TSL:1	c.1877G>A	p.Arg626His	missense splice_region	Exon 6 of 7	ENSP00000487358.1	Q8N1K5-4
THEMIS	ENST00000852157.1		c.1787G>A	p.Arg596His	missense splice_region	Exon 6 of 7	ENSP00000522216.1

Frequencies

GnomAD3 genomes

AF:

0.0000658

AC:

AN:

151890

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:

0.000194

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000561

AC:

AN:

249372

AF XY:

0.0000445

show subpopulations

Gnomad AFR exome

AF:

0.0000622

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000547

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000884

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000459

AC:

AN:

1458996

Hom.:

Cov.:

AF XY:

0.0000482

AC XY:

AN XY:

725832

show subpopulations

African (AFR)

AF:

0.0000601

AC:

AN:

33278

American (AMR)

AF:

0.00

AC:

AN:

44390

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26036

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39606

South Asian (SAS)

AF:

0.0000582

AC:

AN:

85874

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.000522

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.0000486

AC:

AN:

1110434

Other (OTH)

AF:

0.0000332

AC:

AN:

60242

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

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:

0.0000658

AC:

AN:

152008

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41504

American (AMR)

AF:

0.00

AC:

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000195

AC:

AN:

5138

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

67914

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.530

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:

0.000102

Hom.:

Bravo

AF:

0.0000529

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.000110

EpiControl

AF:

0.000298

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.10

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.53

LIST_S2

Benign

0.47

M_CAP

Benign

0.0078

MetaRNN

Benign

0.041

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.34

PhyloP100

0.52

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.83

REVEL

Benign

0.036

Sift

Benign

0.21

Sift4G

Benign

0.16

Polyphen

0.0

Vest4

0.082

MVP

0.27

ClinPred

0.043

GERP RS

3.3

Varity_R

0.041

gMVP

0.11

Mutation Taster

=86/14

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00070

dbscSNV1_RF

Benign

0.046

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

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over