NM_001395362.2:c.293T>C

Variant names:

• chrX-112455021-T-C
• rs1052305471
• NM_001395362.2:c.293T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001395362.2(RTL4):​c.293T>C​(p.Leu98Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000894 in 111,795 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L98I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: RTL4 NM_001395362.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0200
• Publications: 0 publications found

Genes affected

RTL4 (HGNC:25214): (retrotransposon Gag like 4) Predicted to enable nucleic acid binding activity and zinc ion binding activity. Predicted to act upstream of or within cognition and norepinephrine metabolic process. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.877

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001395362.2. 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
	RTL4	NM_001395362.2	MANE Select	c.293T>C	p.Leu98Pro	missense	Exon 5 of 5	NP_001382291.1	Q6ZR62
	RTL4	NM_001004308.3		c.293T>C	p.Leu98Pro	missense	Exon 3 of 3	NP_001004308.2	Q6ZR62

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTL4	ENST00000695839.1	MANE Select	c.293T>C	p.Leu98Pro	missense	Exon 5 of 5	ENSP00000512211.1	Q6ZR62
	RTL4	ENST00000340433.4	TSL:6	c.293T>C	p.Leu98Pro	missense	Exon 4 of 4	ENSP00000340590.2	Q6ZR62
	RTL4	ENST00000695808.1		c.293T>C	p.Leu98Pro	missense	Exon 3 of 3	ENSP00000512188.1	Q6ZR62

Frequencies

GnomAD3 genomes AF: 0.00000894 AC: 1 AN: 111795 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

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: 0.000668

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1098165 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 363553

African (AFR) AF: 0.00 AC: 0 AN: 26402

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19385

East Asian (EAS) AF: 0.00 AC: 0 AN: 30179

South Asian (SAS) AF: 0.00 AC: 0 AN: 54147

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40525

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 842086

Other (OTH) AF: 0.00 AC: 0 AN: 46097

GnomAD4 genome AF: 0.00000894 AC: 1 AN: 111795 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33963

African (AFR) AF: 0.00 AC: 0 AN: 30707

American (AMR) AF: 0.00 AC: 0 AN: 10578

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2646

East Asian (EAS) AF: 0.00 AC: 0 AN: 3529

South Asian (SAS) AF: 0.00 AC: 0 AN: 2655

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6068

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53190

Other (OTH) AF: 0.000668 AC: 1 AN: 1497

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000378

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	0.14
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.12	T
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.29	T
M_CAP	Benign	0.010	T
MetaRNN	Pathogenic	0.88	D
MetaSVM	Benign	-1.0	T
PhyloP100		-0.020
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.24
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.085	T
Polyphen		0.80	P
Vest4		0.60
MutPred		0.74		Loss of stability (P = 0.0012)
MVP		0.47
MPC		0.061
ClinPred		0.41	T
GERP RS		-2.8
Varity_R		0.57
gMVP		0.73
Mutation Taster		=100/0	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: rs1052305471; hg19: chrX-111698249;