6-149889929-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 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, single submitter U:1
• Conservation: PhyloP100: 2.80

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]

RAET1E-LRP11 (HGNC:):

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

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAET1E	NM_001394057.1	c.302T>C	p.Leu101Pro	missense_variant	4/6	ENST00000357183.9
RAET1E-LRP11	NR_182438.1	n.720T>C		non_coding_transcript_exon_variant	3/15
RAET1E-AS1	NR_045126.1	n.885+25547A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAET1E	ENST00000357183.9	c.302T>C	p.Leu101Pro	missense_variant	4/6	1	NM_001394057.1	P2
RAET1E-AS1	ENST00000605899.1	n.114+4256A>G		intron_variant, non_coding_transcript_variant		5
RAET1E-AS1	ENST00000606915.1	n.889+25547A>G		intron_variant, non_coding_transcript_variant		1

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 02, 2021

The c.302T>C (p.L101P) alteration is located in exon 1 (coding exon 1) of the RAET1E gene. This alteration results from a T to C substitution at nucleotide position 302, causing the leucine (L) at amino acid position 101 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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
Eigen	Benign	0.11
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.096	N
LIST_S2	Benign	0.69	T;T;T;T
M_CAP	Benign	0.0061	T
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-6.3	D;D;D;D
REVEL	Benign	0.28
Sift	Uncertain	0.013	D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.83
MutPred		0.81		Gain of disorder (P = 0.0615);Gain of disorder (P = 0.0615);.;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1777804849; hg19: chr6-150211065;