X-72130447-C-T

Variant names:

• chrX-72130447-C-T
• rs755935647
• ENST00000609883.3:c.1094G>A

Variant summary

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

The ENST00000609883.3(RTL5):​c.1094G>A​(p.Arg365His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000581 in 1,205,428 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R365P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000091 (0 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 0.0000055 (0 hom. 3 hem.)
• Consequence: RTL5 ENST00000609883.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.929
• 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.031849265).
• BS2: High Hemizygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHSL2	NM_001013627.3	c.281-1632C>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.1094G>A	p.Arg365His	missense_variant	Exon 1 of 1	6		ENSP00000476792.1
NHSL2	ENST00000633930.2	c.281-1632C>T		intron_variant	Intron 1 of 7	5	NM_001013627.3	ENSP00000488668.1

Frequencies

GnomAD3 genomes AF: 0.00000908 AC: 1 AN: 110192 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000379

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

GnomAD2 exomes AF: 0.0000117 AC: 2 AN: 171657 AF XY: 0.0000337

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000137

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 AF: 0.00000548 AC: 6 AN: 1095236 Hom.: 0 Cov.: 33 AF XY: 0.00000831 AC XY: 3 AN XY: 361120

African (AFR) AF: 0.00 AC: 0 AN: 26346

American (AMR) AF: 0.00 AC: 0 AN: 34741

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19321

East Asian (EAS) AF: 0.00 AC: 0 AN: 30137

South Asian (SAS) AF: 0.0000558 AC: 3 AN: 53790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40345

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4102

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 840469

Other (OTH) AF: 0.0000217 AC: 1 AN: 45985

GnomAD4 genome AF: 0.00000908 AC: 1 AN: 110192 Hom.: 0 Cov.: 22 AF XY: 0.0000309 AC XY: 1 AN XY: 32394

African (AFR) AF: 0.00 AC: 0 AN: 30129

American (AMR) AF: 0.00 AC: 0 AN: 10288

Ashkenazi Jewish (ASJ) AF: 0.000379 AC: 1 AN: 2637

East Asian (EAS) AF: 0.00 AC: 0 AN: 3541

South Asian (SAS) AF: 0.00 AC: 0 AN: 2513

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5843

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52855

Other (OTH) AF: 0.00 AC: 0 AN: 1467

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000248 AC: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	1.4
DANN	Benign	0.92
DEOGEN2	Benign	0.0069	T
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.032	T
MetaSVM	Benign	-0.96	T
PhyloP100		-0.93
PrimateAI	Benign	0.20	T
Sift4G	Benign	0.30	T
Polyphen		0.0010	B
Vest4		0.020
MutPred		0.32		Gain of glycosylation at K364 (P = 0.1075);
MVP		0.014
ClinPred		0.021	T
GERP RS		-0.13
Varity_R		0.027
gMVP		0.15
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: rs755935647; hg19: chrX-71350297; COSMIC: COSV101030113; COSMIC: COSV101030113;