X-72130282-C-T

Variant names:

• chrX-72130282-C-T
• rs1306396186
• ENST00000609883.3:c.1259G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The ENST00000609883.3(RTL5):​c.1259G>A​(p.Ser420Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000168 in 1,192,523 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. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S420R) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0000092 (0 hom., 0 hem., cov: 21)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: RTL5 ENST00000609883.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.206
• 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: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.045114756).
• BP6: Variant X-72130282-C-T is Benign according to our data. Variant chrX-72130282-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3156919.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHSL2	NM_001013627.3	c.281-1797C>T		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.1259G>A	p.Ser420Asn	missense_variant	Exon 1 of 1	6		ENSP00000476792.1
NHSL2	ENST00000633930.2	c.281-1797C>T		intron_variant	Intron 1 of 7	5	NM_001013627.3	ENSP00000488668.1

Frequencies

GnomAD3 genomes AF: 0.00000918 AC: 1 AN: 108951 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.0000336

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 9.23e-7 AC: 1 AN: 1083572 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 350130

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26106

American (AMR) AF: 0.00 AC: 0 AN: 35156

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19260

East Asian (EAS) AF: 0.00 AC: 0 AN: 30138

South Asian (SAS) AF: 0.0000186 AC: 1 AN: 53759

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40480

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4099

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 828977

Other (OTH) AF: 0.00 AC: 0 AN: 45597

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000918 AC: 1 AN: 108951 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 31327

African (AFR) AF: 0.0000336 AC: 1 AN: 29782

American (AMR) AF: 0.00 AC: 0 AN: 10210

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2603

East Asian (EAS) AF: 0.00 AC: 0 AN: 3465

South Asian (SAS) AF: 0.00 AC: 0 AN: 2434

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5711

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52365

Other (OTH) AF: 0.00 AC: 0 AN: 1470

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jan 04, 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	0.052
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.21
DANN	Benign	0.41
DEOGEN2	Benign	0.00073	T
FATHMM_MKL	Benign	0.0051	N
LIST_S2	Benign	0.29	T
M_CAP	Benign	0.0018	T
MetaRNN	Benign	0.045	T
MetaSVM	Benign	-0.94	T
PhyloP100		0.21
PrimateAI	Benign	0.30	T
Sift4G	Benign	0.20	T
Polyphen		0.0	B
Vest4		0.041
MutPred		0.17		Loss of phosphorylation at S420 (P = 3e-04);
MVP		0.014
ClinPred		0.022	T
GERP RS		-1.9
Varity_R		0.051
gMVP		0.016
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: rs1306396186; hg19: chrX-71350132;