6-127719733-C-T

Variant names:

• chr6-127719733-C-T
• rs150338840
• NM_001010923.3:c.1849G>A

Variant summary

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

The NM_001010923.3(THEMIS):​c.1849G>A​(p.Asp617Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000142 in 1,612,156 control chromosomes in the GnomAD database, including 1 homozygotes. 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 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (1 hom.)
• Consequence: THEMIS NM_001010923.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0490
• Publications: 3 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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.007616371).

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.1849G>A	p.Asp617Asn	missense	Exon 5 of 6	NP_001010923.1	Q8N1K5-1
	THEMIS	NM_001164685.2		c.1966G>A	p.Asp656Asn	missense	Exon 6 of 7	NP_001158157.1	Q8N1K5-4
	THEMIS	NM_001394520.1		c.1771G>A	p.Asp591Asn	missense	Exon 6 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.1849G>A	p.Asp617Asn	missense	Exon 5 of 6	ENSP00000357231.2	Q8N1K5-1
	THEMIS	ENST00000630369.2	TSL:1	c.1966G>A	p.Asp656Asn	missense	Exon 6 of 7	ENSP00000487358.1	Q8N1K5-4
	THEMIS	ENST00000852157.1		c.1876G>A	p.Asp626Asn	missense	Exon 6 of 7	ENSP00000522216.1

Frequencies

GnomAD3 genomes AF: 0.0000921 AC: 14 AN: 151940 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000224 AC: 56 AN: 250406 AF XY: 0.000236

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00478

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000617

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000147 AC: 215 AN: 1460216 Hom.: 1 Cov.: 33 AF XY: 0.000142 AC XY: 103 AN XY: 726448

African (AFR) AF: 0.00 AC: 0 AN: 33336

American (AMR) AF: 0.00 AC: 0 AN: 44570

Ashkenazi Jewish (ASJ) AF: 0.00603 AC: 157 AN: 26054

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 86132

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.0000333 AC: 37 AN: 1111006

Other (OTH) AF: 0.000315 AC: 19 AN: 60306

GnomAD4 genome AF: 0.0000921 AC: 14 AN: 151940 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74192

African (AFR) AF: 0.00 AC: 0 AN: 41418

American (AMR) AF: 0.00 AC: 0 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67928

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000189 Hom.: 0

Bravo AF: 0.0000982

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000181 AC: 22

EpiCase AF: 0.000109

EpiControl AF: 0.0000594

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	0.068
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.5
DANN	Benign	0.95
DEOGEN2	Benign	0.060	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.0076	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.46	N
PhyloP100		0.049
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.38	N
REVEL	Benign	0.052
Sift	Benign	0.23	T
Sift4G	Benign	0.45	T
Polyphen		0.0	B
Vest4		0.069
MVP		0.29
ClinPred		0.013	T
GERP RS		-3.0
Varity_R		0.046
gMVP		0.068
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs150338840; hg19: chr6-128040878;