X-78657904-A-G

Position:

• chrX-78657904-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_152694.3(RTL3):​c.517T>C​(p.Tyr173His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: RTL3 NM_152694.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.718

Genes affected

RTL3 (HGNC:22997): (retrotransposon Gag like 3) This gene is a member of a family of gag-related retrotransposon genes. These genes appear to have lost the ability to retrotranspose; however, their open reading frames have remained intact, which may indicate that these genes have acquired new functions in the cell. [provided by RefSeq, Nov 2009]

LOC107985670 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.034050733).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RTL3	NM_152694.3	c.517T>C	p.Tyr173His	missense_variant	2/2	ENST00000321110.2	NP_689907.1
LOC107985670	XR_001755900.2	n.56+4390A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RTL3	ENST00000321110.2	c.517T>C	p.Tyr173His	missense_variant	2/2	2	NM_152694.3	ENSP00000316794.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.00000563 AC: 1 AN: 177731 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 63205

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000746

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 07, 2021

The c.517T>C (p.Y173H) alteration is located in exon 2 (coding exon 1) of the ZCCHC5 gene. This alteration results from a T to C substitution at nucleotide position 517, causing the tyrosine (Y) at amino acid position 173 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.70
DANN	Benign	0.32
DEOGEN2	Benign	0.0011	T
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.32	T
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.034	T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.18	N
REVEL	Benign	0.010
Sift	Benign	0.50	T
Sift4G	Benign	0.56	T
Polyphen		0.0	B
Vest4		0.037
MutPred		0.30		Loss of phosphorylation at Y173 (P = 0.0148);
MVP		0.13
MPC		0.0012
ClinPred		0.025	T
GERP RS		0.64
Varity_R		0.055
gMVP		0.069

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

Publications

LitVar

Other links and lift over

dbSNP: rs750181293; hg19: chrX-77913401;