Variant X-112454804-C-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_001395362.2(RTL4):c.76C>T(p.Arg26Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000192 in 1,207,227 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 65 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R26Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.00019 ( 0 hom. 63 hem. )

Consequence

RTL4
NM_001395362.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.231

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12752032).

BS2

High Hemizygotes in GnomAd at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RTL4	NM_001395362.2 linkuse as main transcript	c.76C>T	p.Arg26Trp	missense_variant	5/5	ENST00000695839.1
RTL4	NM_001004308.3 linkuse as main transcript	c.76C>T	p.Arg26Trp	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Appris
RTL4	ENST00000695839.1 linkuse as main transcript	c.76C>T	p.Arg26Trp	missense_variant	5/5	NM_001395362.2	P1
RTL4	ENST00000340433.4 linkuse as main transcript	c.76C>T	p.Arg26Trp	missense_variant	4/4		P1
RTL4	ENST00000695808.1 linkuse as main transcript	c.76C>T	p.Arg26Trp	missense_variant	3/3		P1

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

111269

Hom.:

Cov.:

AF XY:

0.0000598

AC XY:

AN XY:

33455

show subpopulations

Gnomad AFR

AF:

0.000131

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000286

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:

0.000226

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000671

AC:

AN:

178858

Hom.:

AF XY:

0.0000783

AC XY:

AN XY:

63840

show subpopulations

Gnomad AFR exome

AF:

0.000152

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000141

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000999

Gnomad OTH exome

AF:

0.000227

GnomAD4 exome

AF:

0.000194

AC:

213

AN:

1095908

Hom.:

Cov.:

AF XY:

0.000174

AC XY:

AN XY:

361586

show subpopulations

Gnomad4 AFR exome

AF:

0.0000380

Gnomad4 AMR exome

AF:

0.000115

Gnomad4 ASJ exome

AF:

0.0000521

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000239

Gnomad4 OTH exome

AF:

0.000109

GnomAD4 genome

AF:

0.000171

AC:

AN:

111319

Hom.:

Cov.:

AF XY:

0.0000597

AC XY:

AN XY:

33517

show subpopulations

Gnomad4 AFR

AF:

0.000131

Gnomad4 AMR

AF:

0.000286

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000226

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000238

Hom.:

Bravo

AF:

0.000166

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000741

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 15, 2023

The c.76C>T (p.R26W) alteration is located in exon 3 (coding exon 1) of the ZCCHC16 gene. This alteration results from a C to T substitution at nucleotide position 76, causing the arginine (R) at amino acid position 26 to be replaced by a tryptophan (W). 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

0.10

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.71

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.036

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.60

M_CAP

Uncertain

0.096

MetaRNN

Benign

0.13

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

PrimateAI

Benign

0.19

PROVEAN

Benign

-2.2

REVEL

Benign

0.047

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.015

Polyphen

0.99

Vest4

0.14

MVP

0.62

MPC

0.039

ClinPred

0.093

GERP RS

0.18

Varity_R

0.098

gMVP

0.17

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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