X-112455083-A-G

Variant names:

• chrX-112455083-A-G
• rs777546457
• NM_001395362.2:c.355A>G

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.355A>G​(p.Ser119Gly) 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 1,098,086 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. 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. S119C) has been classified 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: Not reported in ClinVar
• Conservation: PhyloP100: 0.398
• 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=0.07464561).

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.355A>G	p.Ser119Gly	missense	Exon 5 of 5	NP_001382291.1	Q6ZR62
	RTL4	NM_001004308.3		c.355A>G	p.Ser119Gly	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.355A>G	p.Ser119Gly	missense	Exon 5 of 5	ENSP00000512211.1	Q6ZR62
	RTL4	ENST00000340433.4	TSL:6	c.355A>G	p.Ser119Gly	missense	Exon 4 of 4	ENSP00000340590.2	Q6ZR62
	RTL4	ENST00000695808.1		c.355A>G	p.Ser119Gly	missense	Exon 3 of 3	ENSP00000512188.1	Q6ZR62

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.00000546 AC: 1 AN: 182990 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1098086 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 363468

African (AFR) AF: 0.00 AC: 0 AN: 26400

American (AMR) AF: 0.00 AC: 0 AN: 35205

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 30185

South Asian (SAS) AF: 0.00 AC: 0 AN: 54141

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 842008

Other (OTH) AF: 0.00 AC: 0 AN: 46094

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.96
CADD	Benign	3.0
DANN	Benign	0.89
DEOGEN2	Benign	0.032	T
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.28	T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.075	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.40
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.013
Sift	Benign	0.087	T
Sift4G	Benign	0.45	T
Polyphen		0.0040	B
Vest4		0.029
MutPred		0.35		Gain of catalytic residue at S119 (P = 0.0649)
MVP		0.22
MPC		0.013
ClinPred		0.027	T
GERP RS		2.8
Varity_R		0.097
gMVP		0.19
Mutation Taster		=97/3	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: rs777546457; hg19: chrX-111698311; COSMIC: COSV105904264;