Genetic Variant NM_001105556.3:c.7C>T (chr1-27872578-C-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_001105556.3(THEMIS2):c.7C>T(p.Pro3Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000224 in 1,337,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P3A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

THEMIS2
NM_001105556.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.399

Publications

1 publications found

Variant links:

Genes affected

THEMIS2 (HGNC:16839): (thymocyte selection associated family member 2) Predicted to be involved in T cell receptor signaling pathway and regulation of B cell activation. Predicted to be active in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

THEMIS2 links:

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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=0.09475377).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001105556.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
THEMIS2	NM_001105556.3	MANE Select	c.7C>T	p.Pro3Ser	missense	Exon 1 of 6	NP_001099026.1	Q5TEJ8-1
THEMIS2	NM_001286113.2		c.7C>T	p.Pro3Ser	missense	Exon 1 of 7	NP_001273042.1	Q5TEJ8-5
THEMIS2	NM_001286115.2		c.7C>T	p.Pro3Ser	missense	Exon 1 of 6	NP_001273044.1	Q5TEJ8-6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
THEMIS2	ENST00000373921.8	TSL:5 MANE Select	c.7C>T	p.Pro3Ser	missense	Exon 1 of 6	ENSP00000363031.3	Q5TEJ8-1
THEMIS2	ENST00000373925.5	TSL:1	c.7C>T	p.Pro3Ser	missense	Exon 1 of 5	ENSP00000363035.1	Q5TEJ8-2
THEMIS2	ENST00000373927.7	TSL:1	c.7C>T	p.Pro3Ser	missense	Exon 1 of 4	ENSP00000363037.3	Q5TEJ8-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000110

AC:

AN:

91062

AF XY:

0.0000193

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000548

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.00000224

AC:

AN:

1337022

Hom.:

Cov.:

AF XY:

0.00000151

AC XY:

AN XY:

660092

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

27616

American (AMR)

AF:

0.00

AC:

AN:

30120

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23652

East Asian (EAS)

AF:

0.00

AC:

AN:

29322

South Asian (SAS)

AF:

0.00

AC:

AN:

75360

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36252

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5224

European-Non Finnish (NFE)

AF:

0.00000190

AC:

AN:

1054244

Other (OTH)

AF:

0.0000181

AC:

AN:

55232

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000000000888178), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.392

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

Cov.:

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

0.13

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.072

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.37

LIST_S2

Benign

0.82

M_CAP

Benign

0.041

MetaRNN

Benign

0.095

MetaSVM

Benign

-0.78

MutationAssessor

Benign

2.0

PhyloP100

0.40

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.044

Sift

Pathogenic

0.0

Sift4G

Benign

0.15

Polyphen

0.29

Vest4

0.12

MutPred

0.30

Loss of catalytic residue at P3 (P = 0.0247)

MVP

0.22

MPC

0.41

ClinPred

0.31

GERP RS

3.0

PromoterAI

0.17

Neutral

(source)

Varity_R

0.17

gMVP

0.30

Mutation Taster

=84/16

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over