Genetic Variant RTL4:p.Pro191Arg (chrX-112455300-C-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001395362.2(RTL4):c.572C>G(p.Pro191Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000127 in 1,209,538 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 47 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: 𝑓 0.000063 ( 0 hom., 2 hem., cov: 22)

Exomes 𝑓: 0.00013 ( 0 hom. 45 hem. )

Consequence

RTL4
NM_001395362.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.198

Variant links:

Genes affected

RTL4 (HGNC:25214): (retrotransposon Gag like 4) Predicted to enable nucleic acid binding activity and zinc ion binding activity. Predicted to act upstream of or within cognition and norepinephrine metabolic process. [provided by Alliance of Genome Resources, Apr 2022]

RTL4 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07087791).

BS2

High Hemizygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTL4	NM_001395362.2 link	c.572C>G	p.Pro191Arg	missense_variant	Exon 5 of 5	ENST00000695839.1	NP_001382291.1
RTL4	NM_001004308.3 link	c.572C>G	p.Pro191Arg	missense_variant	Exon 3 of 3		NP_001004308.2	Q6ZR62

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RTL4	ENST00000695839.1 link	c.572C>G	p.Pro191Arg	missense_variant	Exon 5 of 5		NM_001395362.2	ENSP00000512211.1	Q6ZR62
RTL4	ENST00000340433.4 link	c.572C>G	p.Pro191Arg	missense_variant	Exon 4 of 4	6		ENSP00000340590.2	Q6ZR62
RTL4	ENST00000695808.1 link	c.572C>G	p.Pro191Arg	missense_variant	Exon 3 of 3			ENSP00000512188.1	Q6ZR62

Frequencies

GnomAD3 genomes

AF:

0.0000628

AC:

AN:

111525

Hom.:

Cov.:

AF XY:

0.0000593

AC XY:

AN XY:

33717

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000494

AC:

AN:

182313

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

67149

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000111

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000134

AC:

147

AN:

1098013

Hom.:

Cov.:

AF XY:

0.000124

AC XY:

AN XY:

363397

show subpopulations

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:

0.000169

Gnomad4 OTH exome

AF:

0.000108

GnomAD4 genome

AF:

0.0000628

AC:

AN:

111525

Hom.:

Cov.:

AF XY:

0.0000593

AC XY:

AN XY:

33717

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000680

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.572C>G (p.P191R) alteration is located in exon 3 (coding exon 1) of the ZCCHC16 gene. This alteration results from a C to G substitution at nucleotide position 572, causing the proline (P) at amino acid position 191 to be replaced by an arginine (R). 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

0.11

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.78

CADD

Benign

7.8

DANN

Benign

0.78

DEOGEN2

Benign

0.023

FATHMM_MKL

Benign

0.033

LIST_S2

Benign

0.31

M_CAP

Benign

0.0061

MetaRNN

Benign

0.071

MetaSVM

Benign

-0.96

PrimateAI

Benign

0.24

PROVEAN

Benign

-2.4

REVEL

Benign

0.025

Sift

Benign

0.045

Sift4G

Uncertain

0.013

Polyphen

0.23

Vest4

0.11

MVP

0.10

MPC

0.034

ClinPred

0.084

GERP RS

2.3

Varity_R

0.067

gMVP

0.27

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over