rs375363209

Variant names:

• chr1-27881973-C-A
• NM_001105556.3:c.649C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-27881973-C-A
• chr1-27881973-C-G
• chr1-27881973-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001105556.3(THEMIS2):​c.649C>A​(p.Arg217Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000687 in 1,456,486 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R217C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: THEMIS2 NM_001105556.3 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.56

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THEMIS2	NM_001105556.3	c.649C>A	p.Arg217Ser	missense_variant, splice_region_variant	Exon 4 of 6	ENST00000373921.8	NP_001099026.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THEMIS2	ENST00000373921.8	c.649C>A	p.Arg217Ser	missense_variant, splice_region_variant	Exon 4 of 6	5	NM_001105556.3	ENSP00000363031.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456486 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 724176

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	.;T;T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.80	T;T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.54	D;D;D
MetaSVM	Benign	-0.58	T
MutationAssessor	Pathogenic	3.1	M;.;M
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.6	D;D;D
REVEL	Benign	0.24
Sift	Benign	0.091	T;T;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.88
MutPred		0.48		Loss of MoRF binding (P = 0.0622);.;Loss of MoRF binding (P = 0.0622);
MVP		0.57
MPC		1.2
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.75
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-28208484;