X-78657051-T-G

Position:

• chrX-78657051-T-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_152694.3(RTL3):​c.1370A>C​(p.Asp457Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000082 in 1,098,045 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. 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: 23)
  • Exomes 𝑓: 0.0000082 (0 hom. 2 hem.)
• Consequence: RTL3 NM_152694.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.315

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10983646).
• BS2: High Hemizygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RTL3	NM_152694.3	c.1370A>C	p.Asp457Ala	missense_variant	2/2	ENST00000321110.2	NP_689907.1
LOC107985670	XR_001755900.2	n.56+3537T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RTL3	ENST00000321110.2	c.1370A>C	p.Asp457Ala	missense_variant	2/2	2	NM_152694.3	ENSP00000316794.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000820 AC: 9 AN: 1098045 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 2 AN XY: 363423

Gnomad4 AFR exome AF: 0.0000758

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000152

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000756

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

Nov 27, 2023

The c.1370A>C (p.D457A) alteration is located in exon 2 (coding exon 1) of the ZCCHC5 gene. This alteration results from a A to C substitution at nucleotide position 1370, causing the aspartic acid (D) at amino acid position 457 to be replaced by an alanine (A). 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	0.13
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	12
DANN	Benign	0.96
DEOGEN2	Benign	0.073	T
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.31	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.71	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.15
Sift	Benign	0.23	T
Sift4G	Uncertain	0.055	T
Polyphen		0.065	B
Vest4		0.17
MutPred		0.63		Loss of ubiquitination at K461 (P = 0.0675);
MVP		0.87
MPC		0.0012
ClinPred		0.087	T
GERP RS		0.64
Varity_R		0.18
gMVP		0.32

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: rs988370587; hg19: chrX-77912548;