chr6-149889929-A-G

Variant names:

• chr6-149889929-A-G
• rs1777804849
• NM_001394057.1:c.302T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001394057.1(RAET1E):​c.302T>C​(p.Leu101Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RAET1E NM_001394057.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.80
• Publications: 0 publications found

Genes affected

RAET1E (HGNC:16793): (retinoic acid early transcript 1E) This gene belong to the RAET1 family, which consists of major histocompatibility complex (MHC) class I-related genes located in a cluster on chromosome 6q24.2-q25.3. This and RAET1G protein differ from other RAET1 proteins in that they have type I membrane-spanning sequences at their C termini rather than glycosylphosphatidylinositol anchor sequences. This protein functions as a ligand for NKG2D receptor, which is expressed on the surface of several types of immune cells, and is involved in innate and adaptive immune responses. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Aug 2011]

ENSG00000285991 (HGNC:):

RAET1E-AS1 (HGNC:48994): (RAET1E antisense RNA 1)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001394057.1. 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
	RAET1E	NM_001394057.1	MANE Select	c.302T>C	p.Leu101Pro	missense	Exon 4 of 6	NP_001380986.1	Q8TD07-1
	RAET1E	NM_139165.3		c.302T>C	p.Leu101Pro	missense	Exon 2 of 4	NP_631904.1	Q8TD07-1
	RAET1E	NM_001394056.1		c.302T>C	p.Leu101Pro	missense	Exon 4 of 7	NP_001380985.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAET1E	ENST00000357183.9	TSL:1 MANE Select	c.302T>C	p.Leu101Pro	missense	Exon 4 of 6	ENSP00000349709.4	Q8TD07-1
	RAET1E	ENST00000367363.3	TSL:1	c.194T>C	p.Leu65Pro	missense	Exon 2 of 4	ENSP00000356332.3	Q8TD07-2
	RAET1E	ENST00000532335.5	TSL:1	c.302T>C	p.Leu101Pro	missense	Exon 3 of 5	ENSP00000437067.1	Q8TD07-3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461870 Hom.: 0 Cov.: 38 AF XY: 0.00000138 AC XY: 1 AN XY: 727234

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Benign	0.11
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.096	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0061	T
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-1.0	T
PhyloP100		2.8
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Benign	0.28
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.81		Gain of disorder (P = 0.0615)
MVP		0.43
MPC		0.53
ClinPred		0.84	D
GERP RS		3.7
Varity_R		0.93
gMVP		0.73
Mutation Taster		=85/15	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: rs1777804849; hg19: chr6-150211065;