ENST00000609883.3:c.1168A>G

Variant names:

• chrX-72130373-T-C
• rs1476085101
• ENST00000609883.3:c.1168A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The ENST00000609883.3(RTL5):​c.1168A>G​(p.Lys390Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000055 in 109,180 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. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000055 (0 hom., 4 hem., cov: 21)
  • Exomes 𝑓: 0.0000019 (0 hom. 2 hem.)
  • Failed GnomAD Quality Control
• Consequence: RTL5 ENST00000609883.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.317
• Publications: 0 publications found

Genes affected

RTL5 (HGNC:29430): (retrotransposon Gag like 5)

NHSL2 (HGNC:33737): (NHS like 2) Predicted to enable calcium ion binding activity. Predicted to be involved in cell differentiation. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.038870305).
• BP6: Variant X-72130373-T-C is Benign according to our data. Variant chrX-72130373-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3315667.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHSL2	NM_001013627.3	c.281-1706T>C		intron_variant	Intron 1 of 7	ENST00000633930.2	NP_001013649.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RTL5	ENST00000609883.3	c.1168A>G	p.Lys390Glu	missense_variant	Exon 1 of 1	6		ENSP00000476792.1
NHSL2	ENST00000633930.2	c.281-1706T>C		intron_variant	Intron 1 of 7	5	NM_001013627.3	ENSP00000488668.1

Frequencies

GnomAD3 genomes AF: 0.0000550 AC: 6 AN: 109180 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000491

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: 0.00

Gnomad OTH AF: 0.000690

GnomAD2 exomes AF: 0.00000698 AC: 1 AN: 143229 AF XY: 0.0000230

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000439

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000189 AC: 2 AN: 1058767 Hom.: 0 Cov.: 29 AF XY: 0.00000600 AC XY: 2 AN XY: 333155

African (AFR) AF: 0.00 AC: 0 AN: 25511

American (AMR) AF: 0.0000317 AC: 1 AN: 31511

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18867

East Asian (EAS) AF: 0.00 AC: 0 AN: 29229

South Asian (SAS) AF: 0.00 AC: 0 AN: 51363

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38945

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4031

European-Non Finnish (NFE) AF: 0.00000123 AC: 1 AN: 814497

Other (OTH) AF: 0.00 AC: 0 AN: 44813

GnomAD4 genome AF: 0.0000550 AC: 6 AN: 109180 Hom.: 0 Cov.: 21 AF XY: 0.000127 AC XY: 4 AN XY: 31560

African (AFR) AF: 0.00 AC: 0 AN: 29910

American (AMR) AF: 0.000491 AC: 5 AN: 10178

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2618

East Asian (EAS) AF: 0.00 AC: 0 AN: 3497

South Asian (SAS) AF: 0.00 AC: 0 AN: 2466

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5737

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 234

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52419

Other (OTH) AF: 0.000690 AC: 1 AN: 1450

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000793

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jun 17, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.15
DANN	Benign	0.53
DEOGEN2	Benign	0.00021	T
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.30	T
M_CAP	Benign	0.00083	T
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-0.96	T
PhyloP100		-0.32
PrimateAI	Benign	0.39	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.097
MutPred		0.30		Loss of methylation at K390 (P = 0.0011);
MVP		0.16
ClinPred		0.020	T
GERP RS		-3.8
Varity_R		0.051
gMVP		0.031
Mutation Taster		=98/2	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: rs1476085101; hg19: chrX-71350223;