X-112455268-G-C

Variant names:

• chrX-112455268-G-C
• NM_001395362.2:c.540G>C

Variant summary

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

The NM_001395362.2(RTL4):​c.540G>C​(p.Gln180His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,938 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: RTL4 NM_001395362.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.44
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.077276856).

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.540G>C	p.Gln180His	missense	Exon 5 of 5	NP_001382291.1	Q6ZR62
	RTL4	NM_001004308.3		c.540G>C	p.Gln180His	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.540G>C	p.Gln180His	missense	Exon 5 of 5	ENSP00000512211.1	Q6ZR62
	RTL4	ENST00000340433.4	TSL:6	c.540G>C	p.Gln180His	missense	Exon 4 of 4	ENSP00000340590.2	Q6ZR62
	RTL4	ENST00000695808.1		c.540G>C	p.Gln180His	missense	Exon 3 of 3	ENSP00000512188.1	Q6ZR62

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097938 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 363326

African (AFR) AF: 0.00 AC: 0 AN: 26401

American (AMR) AF: 0.00 AC: 0 AN: 35193

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19360

East Asian (EAS) AF: 0.00 AC: 0 AN: 30187

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54066

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40513

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841997

Other (OTH) AF: 0.00 AC: 0 AN: 46087

GnomAD4 genome Cov.: 22

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	0.12
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	3.0
DANN	Benign	0.59
DEOGEN2	Benign	0.025	T
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.077	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.4
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.025
Sift	Benign	0.33	T
Sift4G	Uncertain	0.012	D
Polyphen		0.0090	B
Vest4		0.087
MutPred		0.30		Gain of catalytic residue at Q180 (P = 0.0607)
MVP		0.32
MPC		0.014
ClinPred		0.062	T
GERP RS		3.2
Varity_R		0.12
gMVP		0.61
Mutation Taster		=99/1	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

hg19: chrX-111698496;