6-127812908-G-A

Variant names:

• chr6-127812908-G-A
• rs370574765
• NM_001010923.3:c.1733C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001010923.3(THEMIS):​c.1733C>T​(p.Thr578Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,610,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: THEMIS NM_001010923.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.423
• Publications: 2 publications found

Genes affected

THEMIS (HGNC:21569): (thymocyte selection associated) This gene encodes a protein that plays a regulatory role in both positive and negative T-cell selection during late thymocyte development. The protein functions through T-cell antigen receptor signaling, and is necessary for proper lineage commitment and maturation of T-cells. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0734134).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001010923.3. 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
	THEMIS	NM_001010923.3	MANE Select	c.1733C>T	p.Thr578Met	missense	Exon 4 of 6	NP_001010923.1	Q8N1K5-1
	THEMIS	NM_001164685.2		c.1733C>T	p.Thr578Met	missense	Exon 4 of 7	NP_001158157.1	Q8N1K5-4
	THEMIS	NM_001394520.1		c.1655C>T	p.Thr552Met	missense	Exon 5 of 7	NP_001381449.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THEMIS	ENST00000368248.5	TSL:1 MANE Select	c.1733C>T	p.Thr578Met	missense	Exon 4 of 6	ENSP00000357231.2	Q8N1K5-1
	THEMIS	ENST00000630369.2	TSL:1	c.1733C>T	p.Thr578Met	missense	Exon 4 of 7	ENSP00000487358.1	Q8N1K5-4
	THEMIS	ENST00000852157.1		c.1760C>T	p.Thr587Met	missense	Exon 5 of 7	ENSP00000522216.1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000265

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: 0.00

GnomAD2 exomes AF: 0.0000242 AC: 6 AN: 248030 AF XY: 0.0000299

Gnomad AFR exome AF: 0.000370

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1457826 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 724912

African (AFR) AF: 0.000330 AC: 11 AN: 33362

American (AMR) AF: 0.0000225 AC: 1 AN: 44450

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25710

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.0000234 AC: 2 AN: 85652

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53242

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109800

Other (OTH) AF: 0.00 AC: 0 AN: 60214

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152246 Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74442

African (AFR) AF: 0.000265 AC: 11 AN: 41554

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000987 Hom.: 0

Bravo AF: 0.000117

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

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	0.080
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	8.8
DANN	Benign	0.91
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.073	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.97	L
PhyloP100		0.42
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.95	N
REVEL	Benign	0.11
Sift	Uncertain	0.011	D
Sift4G	Benign	0.11	T
Polyphen		0.91	P
Vest4		0.14
MVP		0.24
ClinPred		0.058	T
GERP RS		-2.6
Varity_R		0.026
gMVP		0.19
Mutation Taster		=97/3	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: rs370574765; hg19: chr6-128134053; COSMIC: COSV64073823; COSMIC: COSV64073823;