X-78657144-A-G

Position:

• chrX-78657144-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.1277T>C​(p.Ile426Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,098,235 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. 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: 9.1e-7 (0 hom. 0 hem.)
• Consequence: RTL3 NM_152694.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.663

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=0.055326194).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RTL3	NM_152694.3	c.1277T>C	p.Ile426Thr	missense_variant	2/2	ENST00000321110.2	NP_689907.1
LOC107985670	XR_001755900.2	n.56+3630A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RTL3	ENST00000321110.2	c.1277T>C	p.Ile426Thr	missense_variant	2/2	2	NM_152694.3	ENSP00000316794.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1098235 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 363603

Gnomad4 AFR exome AF: 0.00

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: 0.00000119

Gnomad4 OTH exome AF: 0.00

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

Apr 07, 2022

The c.1277T>C (p.I426T) 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 1277, causing the isoleucine (I) at amino acid position 426 to be replaced by a threonine (T). 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	0.091
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	3.5
DANN	Benign	0.25
DEOGEN2	Benign	0.0021	T
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.31	T
M_CAP	Benign	0.0016	T
MetaRNN	Benign	0.055	T
MetaSVM	Benign	-0.98	T
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.83	N
REVEL	Benign	0.011
Sift	Benign	0.36	T
Sift4G	Benign	0.45	T
Polyphen		0.017	B
Vest4		0.033
MutPred		0.30		Gain of glycosylation at I426 (P = 0.0288);
MVP		0.099
MPC		0.0012
ClinPred		0.060	T
GERP RS		2.3
Varity_R		0.028
gMVP		0.10

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: rs1923011577; hg19: chrX-77912641;