NM_001395362.2:c.14C>T

Variant names:

• chrX-112454742-C-T
• rs768703027
• NM_001395362.2:c.14C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001395362.2(RTL4):​c.14C>T​(p.Thr5Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000751 in 1,184,764 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 34 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 0.000045 (0 hom., 3 hem., cov: 23)
  • Exomes 𝑓: 0.000078 (0 hom. 31 hem.)
• Consequence: RTL4 NM_001395362.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.478
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06585014).
• BS2: High Hemizygotes in GnomAd4 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.14C>T	p.Thr5Met	missense	Exon 5 of 5	NP_001382291.1	Q6ZR62
	RTL4	NM_001004308.3		c.14C>T	p.Thr5Met	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.14C>T	p.Thr5Met	missense	Exon 5 of 5	ENSP00000512211.1	Q6ZR62
	RTL4	ENST00000340433.4	TSL:6	c.14C>T	p.Thr5Met	missense	Exon 4 of 4	ENSP00000340590.2	Q6ZR62
	RTL4	ENST00000695808.1		c.14C>T	p.Thr5Met	missense	Exon 3 of 3	ENSP00000512188.1	Q6ZR62

Frequencies

GnomAD3 genomes AF: 0.0000447 AC: 5 AN: 111768 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000651

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: 0.0000376

Gnomad OTH AF: 0.000669

GnomAD2 exomes AF: 0.0000319 AC: 5 AN: 156624 AF XY: 0.0000401

Gnomad AFR exome AF: 0.000156

Gnomad AMR exome AF: 0.0000844

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000141

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000783 AC: 84 AN: 1072996 Hom.: 0 Cov.: 29 AF XY: 0.0000892 AC XY: 31 AN XY: 347686

African (AFR) AF: 0.000273 AC: 7 AN: 25629

American (AMR) AF: 0.0000625 AC: 2 AN: 32013

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17458

East Asian (EAS) AF: 0.00 AC: 0 AN: 29990

South Asian (SAS) AF: 0.0000202 AC: 1 AN: 49547

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39668

Middle Eastern (MID) AF: 0.000754 AC: 3 AN: 3980

European-Non Finnish (NFE) AF: 0.0000820 AC: 68 AN: 829772

Other (OTH) AF: 0.0000668 AC: 3 AN: 44939

GnomAD4 genome AF: 0.0000447 AC: 5 AN: 111768 Hom.: 0 Cov.: 23 AF XY: 0.0000884 AC XY: 3 AN XY: 33932

African (AFR) AF: 0.0000651 AC: 2 AN: 30714

American (AMR) AF: 0.00 AC: 0 AN: 10536

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2650

East Asian (EAS) AF: 0.00 AC: 0 AN: 3556

South Asian (SAS) AF: 0.00 AC: 0 AN: 2628

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6079

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.0000376 AC: 2 AN: 53187

Other (OTH) AF: 0.000669 AC: 1 AN: 1494

Alfa AF: 0.0000681 Hom.: 1

Bravo AF: 0.0000567

ExAC AF: 0.0000248 AC: 3

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	0.094
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.4
DANN	Uncertain	0.98
DEOGEN2	Benign	0.019	T
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.36	T
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.48
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.14
Sift	Benign	0.066	T
Sift4G	Uncertain	0.020	D
Polyphen		0.93	P
Vest4		0.13
MutPred		0.095		Loss of helix (P = 0.0558)
MVP		0.12
MPC		0.087
ClinPred		0.028	T
GERP RS		1.3
PromoterAI		-0.014	Neutral
Varity_R		0.027
gMVP		0.18
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: rs768703027; hg19: chrX-111697970; COSMIC: COSV107424753;