1-27879739-T-C

Variant names:

• chr1-27879739-T-C
• rs41284294
• NM_001105556.3:c.331T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001105556.3(THEMIS2):​c.331T>C​(p.Phe111Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00959 in 1,614,074 control chromosomes in the GnomAD database, including 97 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0073 (6 hom., cov: 31)
  • Exomes 𝑓: 0.0098 (91 hom.)
• Consequence: THEMIS2 NM_001105556.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.83
• Publications: 12 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005374044).
• BP6: Variant 1-27879739-T-C is Benign according to our data. Variant chr1-27879739-T-C is described in ClinVar as Benign. ClinVar VariationId is 777747.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

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.331T>C	p.Phe111Leu	missense	Exon 3 of 6	NP_001099026.1	Q5TEJ8-1
	THEMIS2	NM_001286113.2		c.331T>C	p.Phe111Leu	missense	Exon 3 of 7	NP_001273042.1	Q5TEJ8-5
	THEMIS2	NM_001286115.2		c.331T>C	p.Phe111Leu	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.331T>C	p.Phe111Leu	missense	Exon 3 of 6	ENSP00000363031.3	Q5TEJ8-1
	THEMIS2	ENST00000456990.1	TSL:1	c.7T>C	p.Phe3Leu	missense	Exon 1 of 5	ENSP00000398049.1	H7C124
	THEMIS2	ENST00000373925.5	TSL:1	c.331T>C	p.Phe111Leu	missense	Exon 3 of 5	ENSP00000363035.1	Q5TEJ8-2

Frequencies

GnomAD3 genomes AF: 0.00734 AC: 1116 AN: 152080 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.00142

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00701

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00840

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0114

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.00819 AC: 2059 AN: 251432 AF XY: 0.00789

Gnomad AFR exome AF: 0.00172

Gnomad AMR exome AF: 0.00546

Gnomad ASJ exome AF: 0.0141

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00961

Gnomad NFE exome AF: 0.0122

Gnomad OTH exome AF: 0.00864

GnomAD4 exome AF: 0.00982 AC: 14356 AN: 1461876 Hom.: 91 Cov.: 32 AF XY: 0.00961 AC XY: 6988 AN XY: 727238

African (AFR) AF: 0.00185 AC: 62 AN: 33480

American (AMR) AF: 0.00613 AC: 274 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0154 AC: 402 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00176 AC: 152 AN: 86258

European-Finnish (FIN) AF: 0.0101 AC: 542 AN: 53414

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5768

European-Non Finnish (NFE) AF: 0.0112 AC: 12432 AN: 1112002

Other (OTH) AF: 0.00795 AC: 480 AN: 60394

GnomAD4 genome AF: 0.00733 AC: 1116 AN: 152198 Hom.: 6 Cov.: 31 AF XY: 0.00710 AC XY: 528 AN XY: 74394

African (AFR) AF: 0.00142 AC: 59 AN: 41540

American (AMR) AF: 0.00700 AC: 107 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 53 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4828

European-Finnish (FIN) AF: 0.00840 AC: 89 AN: 10594

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0114 AC: 773 AN: 67984

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.0107 Hom.: 32

Bravo AF: 0.00728

TwinsUK AF: 0.0129 AC: 48

ALSPAC AF: 0.00882 AC: 34

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.0141 AC: 121

ExAC AF: 0.00833 AC: 1011

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0101

EpiControl AF: 0.0116

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.055
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		2.8
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.17
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.048	D
Polyphen		0.87	P
Vest4		0.76
MutPred		0.53		Gain of catalytic residue at F111 (P = 0.0761)
MVP		0.19
MPC		0.93
ClinPred		0.060	T
GERP RS		3.5
PromoterAI		-0.012	Neutral
Varity_R		0.48
gMVP		0.77
Mutation Taster		=87/13	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: rs41284294; hg19: chr1-28206250; COSMIC: COSV99058360; COSMIC: COSV99058360;