chr1-27872578-C-G

Variant names:

• chr1-27872578-C-G
• rs1422209548
• NM_001105556.3:c.7C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001105556.3(THEMIS2):​c.7C>G​(p.Pro3Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000201 in 1,489,034 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. P3S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: THEMIS2 NM_001105556.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.399
• Publications: 1 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06107217).

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.7C>G	p.Pro3Ala	missense	Exon 1 of 6	NP_001099026.1	Q5TEJ8-1
	THEMIS2	NM_001286113.2		c.7C>G	p.Pro3Ala	missense	Exon 1 of 7	NP_001273042.1	Q5TEJ8-5
	THEMIS2	NM_001286115.2		c.7C>G	p.Pro3Ala	missense	Exon 1 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.7C>G	p.Pro3Ala	missense	Exon 1 of 6	ENSP00000363031.3	Q5TEJ8-1
	THEMIS2	ENST00000373925.5	TSL:1	c.7C>G	p.Pro3Ala	missense	Exon 1 of 5	ENSP00000363035.1	Q5TEJ8-2
	THEMIS2	ENST00000373927.7	TSL:1	c.7C>G	p.Pro3Ala	missense	Exon 1 of 4	ENSP00000363037.3	Q5TEJ8-4

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152010 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000110 AC: 1 AN: 91062 AF XY: 0.00

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: 0.00000150 AC: 2 AN: 1337024 Hom.: 0 Cov.: 30 AF XY: 0.00000151 AC XY: 1 AN XY: 660094

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

African (AFR) AF: 0.00 AC: 0 AN: 27616

American (AMR) AF: 0.0000664 AC: 2 AN: 30120

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23652

East Asian (EAS) AF: 0.00 AC: 0 AN: 29322

South Asian (SAS) AF: 0.00 AC: 0 AN: 75360

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36252

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5224

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1054246

Other (OTH) AF: 0.00 AC: 0 AN: 55232

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152010 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74244

African (AFR) AF: 0.00 AC: 0 AN: 41416

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67956

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

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	0.047
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	13
DANN	Benign	0.79
DEOGEN2	Benign	0.070	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.061	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.40
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.050
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.034	D
Polyphen		0.087	B
Vest4		0.15
MutPred		0.30		Loss of catalytic residue at P3 (P = 0.0745)
MVP		0.15
MPC		0.39
ClinPred		0.13	T
GERP RS		3.0
PromoterAI		-0.10	Neutral
Varity_R		0.12
gMVP		0.22
Mutation Taster		=81/19	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: rs1422209548; hg19: chr1-28199089;