6-127719822-C-G

Variant names:

• chr6-127719822-C-G
• rs746600803
• NM_001010923.3:c.1760G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001010923.3(THEMIS):​c.1760G>C​(p.Arg587Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R587H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: THEMIS NM_001010923.3 missense, splice_region
• Scores: Splicing: ADA: 0.001265
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.523
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.121786594).

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.1760G>C	p.Arg587Pro	missense splice_region	Exon 5 of 6	NP_001010923.1	Q8N1K5-1
	THEMIS	NM_001164685.2		c.1877G>C	p.Arg626Pro	missense splice_region	Exon 6 of 7	NP_001158157.1	Q8N1K5-4
	THEMIS	NM_001394520.1		c.1682G>C	p.Arg561Pro	missense splice_region	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.1760G>C	p.Arg587Pro	missense splice_region	Exon 5 of 6	ENSP00000357231.2	Q8N1K5-1
	THEMIS	ENST00000630369.2	TSL:1	c.1877G>C	p.Arg626Pro	missense splice_region	Exon 6 of 7	ENSP00000487358.1	Q8N1K5-4
	THEMIS	ENST00000852157.1		c.1787G>C	p.Arg596Pro	missense splice_region	Exon 6 of 7	ENSP00000522216.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458998 Hom.: 0 Cov.: 33 AF XY: 0.00000276 AC XY: 2 AN XY: 725834

African (AFR) AF: 0.00 AC: 0 AN: 33278

American (AMR) AF: 0.00 AC: 0 AN: 44390

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26036

East Asian (EAS) AF: 0.00 AC: 0 AN: 39606

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85874

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110436

Other (OTH) AF: 0.00 AC: 0 AN: 60242

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.070	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.068	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.52
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.034
Sift	Benign	0.14	T
Sift4G	Benign	0.25	T
Polyphen		0.033	B
Vest4		0.14
MutPred		0.26		Loss of MoRF binding (P = 0.0072)
MVP		0.32
ClinPred		0.57	D
GERP RS		3.3
Varity_R		0.13
gMVP		0.16
Mutation Taster		=70/30	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0013
dbscSNV1_RF	Benign	0.094
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: rs746600803; hg19: chr6-128040967;