chrX-112455083-A-T

Variant names:

• chrX-112455083-A-T
• rs777546457
• NM_001395362.2:c.355A>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.355A>T​(p.Ser119Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000107 in 1,210,084 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 0.000011 (0 hom. 3 hem.)
• Consequence: RTL4 NM_001395362.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2102066).
• BS2: High Hemizygotes in GnomAdExome4 at 3 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.355A>T	p.Ser119Cys	missense	Exon 5 of 5	NP_001382291.1	Q6ZR62
	RTL4	NM_001004308.3		c.355A>T	p.Ser119Cys	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>T	p.Ser119Cys	missense	Exon 5 of 5	ENSP00000512211.1	Q6ZR62
	RTL4	ENST00000340433.4	TSL:6	c.355A>T	p.Ser119Cys	missense	Exon 4 of 4	ENSP00000340590.2	Q6ZR62
	RTL4	ENST00000695808.1		c.355A>T	p.Ser119Cys	missense	Exon 3 of 3	ENSP00000512188.1	Q6ZR62

Frequencies

GnomAD3 genomes AF: 0.00000893 AC: 1 AN: 111998 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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000109 AC: 12 AN: 1098086 Hom.: 0 Cov.: 34 AF XY: 0.00000825 AC XY: 3 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: 0.0000143 AC: 12 AN: 842008

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

GnomAD4 genome AF: 0.00000893 AC: 1 AN: 111998 Hom.: 0 Cov.: 22 AF XY: 0.0000293 AC XY: 1 AN XY: 34152

African (AFR) AF: 0.00 AC: 0 AN: 30775

American (AMR) AF: 0.00 AC: 0 AN: 10580

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3565

South Asian (SAS) AF: 0.00 AC: 0 AN: 2649

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6086

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53265

Other (OTH) AF: 0.00 AC: 0 AN: 1501

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

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	0.095
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.20	T
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.99	T
PhyloP100		0.40
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.076
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.051	T
Polyphen		0.99	D
Vest4		0.21
MVP		0.26
MPC		0.014
ClinPred		0.25	T
GERP RS		2.8
Varity_R		0.17
gMVP		0.29
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

dbSNP: rs777546457; hg19: chrX-111698311;