X-112454804-C-T

Variant names:

• chrX-112454804-C-T
• rs202145443
• NM_001395362.2:c.76C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001395362.2(RTL4):​c.76C>T​(p.Arg26Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000192 in 1,207,227 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 65 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign 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. R26L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.00019 (0 hom. 63 hem.)
• Consequence: RTL4 NM_001395362.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.231
• Publications: 4 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12752032).
• BS2: High Hemizygotes in GnomAd4 at 2 gene

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.76C>T	p.Arg26Trp	missense	Exon 5 of 5	NP_001382291.1	Q6ZR62
	RTL4	NM_001004308.3		c.76C>T	p.Arg26Trp	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.76C>T	p.Arg26Trp	missense	Exon 5 of 5	ENSP00000512211.1	Q6ZR62
	RTL4	ENST00000340433.4	TSL:6	c.76C>T	p.Arg26Trp	missense	Exon 4 of 4	ENSP00000340590.2	Q6ZR62
	RTL4	ENST00000695808.1		c.76C>T	p.Arg26Trp	missense	Exon 3 of 3	ENSP00000512188.1	Q6ZR62

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 19 AN: 111269 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000131

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000286

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: 0.000226

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000671 AC: 12 AN: 178858 AF XY: 0.0000783

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000141

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000999

Gnomad OTH exome AF: 0.000227

GnomAD4 exome AF: 0.000194 AC: 213 AN: 1095908 Hom.: 0 Cov.: 29 AF XY: 0.000174 AC XY: 63 AN XY: 361586

African (AFR) AF: 0.0000380 AC: 1 AN: 26334

American (AMR) AF: 0.000115 AC: 4 AN: 34872

Ashkenazi Jewish (ASJ) AF: 0.0000521 AC: 1 AN: 19212

East Asian (EAS) AF: 0.00 AC: 0 AN: 30174

South Asian (SAS) AF: 0.00 AC: 0 AN: 53590

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40481

Middle Eastern (MID) AF: 0.000243 AC: 1 AN: 4107

European-Non Finnish (NFE) AF: 0.000239 AC: 201 AN: 841138

Other (OTH) AF: 0.000109 AC: 5 AN: 46000

GnomAD4 genome AF: 0.000171 AC: 19 AN: 111319 Hom.: 0 Cov.: 23 AF XY: 0.0000597 AC XY: 2 AN XY: 33517

African (AFR) AF: 0.000131 AC: 4 AN: 30548

American (AMR) AF: 0.000286 AC: 3 AN: 10504

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2636

East Asian (EAS) AF: 0.00 AC: 0 AN: 3512

South Asian (SAS) AF: 0.00 AC: 0 AN: 2582

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6051

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.000226 AC: 12 AN: 53069

Other (OTH) AF: 0.00 AC: 0 AN: 1515

Alfa AF: 0.000237 Hom.: 12

Bravo AF: 0.000166

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000741 AC: 9

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	0.10
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.036	T
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.60	T
M_CAP	Uncertain	0.096	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.23
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.047
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.015	D
Polyphen		0.99	D
Vest4		0.14
MVP		0.62
MPC		0.039
ClinPred		0.093	T
GERP RS		0.18
PromoterAI		0.0051	Neutral
Varity_R		0.098
gMVP		0.17
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs202145443; hg19: chrX-111698032; COSMIC: COSV61206399;