1-27879794-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001105556.3(THEMIS2):c.386T>C(p.Leu129Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 31)
• Consequence: THEMIS2 NM_001105556.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.15

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.043509185).
• BP6: Variant 1-27879794-T-C is Benign according to our data. Variant chr1-27879794-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 2327487.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THEMIS2	NM_001105556.3	c.386T>C	p.Leu129Pro	missense_variant	3/6	ENST00000373921.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THEMIS2	ENST00000373921.8	c.386T>C	p.Leu129Pro	missense_variant	3/6	5	NM_001105556.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 18, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	9.0
Dann	Benign	0.80
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.58	T;T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.044	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.4	N;N;.;N
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Benign	0.31	T
PROVEAN	Benign	1.7	N;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.66	T;T;T;T
Sift4G	Benign	0.20	T;T;T;T
Polyphen		0.0	B;B;.;B
Vest4		0.21
MutPred		0.46		Loss of stability (P = 0.0262);Loss of stability (P = 0.0262);.;Loss of stability (P = 0.0262);
MVP		0.11
MPC		0.59
ClinPred		0.052	T
GERP RS		2.8
Varity_R		0.063
gMVP		0.60

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-28206305;