1-27879886-C-G

Variant names:

• chr1-27879886-C-G
• rs751391949
• NM_001105556.3:c.478C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001105556.3(THEMIS2):​c.478C>G​(p.Pro160Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,680 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: THEMIS2 NM_001105556.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.49
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THEMIS2	NM_001105556.3	MANE Select	c.478C>G	p.Pro160Ala	missense	Exon 3 of 6	NP_001099026.1	Q5TEJ8-1
	THEMIS2	NM_001286113.2		c.478C>G	p.Pro160Ala	missense	Exon 3 of 7	NP_001273042.1	Q5TEJ8-5
	THEMIS2	NM_001286115.2		c.478C>G	p.Pro160Ala	missense	Exon 3 of 6	NP_001273044.1	Q5TEJ8-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THEMIS2	ENST00000373921.8	TSL:5 MANE Select	c.478C>G	p.Pro160Ala	missense	Exon 3 of 6	ENSP00000363031.3	Q5TEJ8-1
	THEMIS2	ENST00000456990.1	TSL:1	c.154C>G	p.Pro52Ala	missense	Exon 1 of 5	ENSP00000398049.1	H7C124
	THEMIS2	ENST00000373925.5	TSL:1	c.478C>G	p.Pro160Ala	missense	Exon 3 of 5	ENSP00000363035.1	Q5TEJ8-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000404 AC: 1 AN: 247508 AF XY: 0.00

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: 0.00000897

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460680 Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 4 AN XY: 726498

African (AFR) AF: 0.00 AC: 0 AN: 33438

American (AMR) AF: 0.00 AC: 0 AN: 44524

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.0000465 AC: 4 AN: 86110

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111388

Other (OTH) AF: 0.00 AC: 0 AN: 60330

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-0.74	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		1.5
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Benign	0.26
Sift	Uncertain	0.020	D
Sift4G	Benign	0.11	T
Polyphen		0.77	P
Vest4		0.53
MutPred		0.52		Loss of glycosylation at P160 (P = 0.0766)
MVP		0.43
MPC		1.1
ClinPred		0.96	D
GERP RS		2.8
PromoterAI		-0.0049	Neutral
Varity_R		0.28
gMVP		0.80
Mutation Taster		=72/28	polymorphism

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

Other links and lift over

dbSNP: rs751391949; hg19: chr1-28206397;