Variant X-112454907-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001395362.2(RTL4):c.179A>G(p.His60Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000571 in 1,208,463 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 23 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 0.00040 ( 0 hom., 14 hem., cov: 22)

Exomes 𝑓: 0.000023 ( 0 hom. 9 hem. )

Consequence

RTL4
NM_001395362.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.32

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 Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012081295).

BS2

High Hemizygotes in GnomAd at 14 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RTL4	NM_001395362.2 linkuse as main transcript	c.179A>G	p.His60Arg	missense_variant	5/5	ENST00000695839.1
RTL4	NM_001004308.3 linkuse as main transcript	c.179A>G	p.His60Arg	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Appris
RTL4	ENST00000695839.1 linkuse as main transcript	c.179A>G	p.His60Arg	missense_variant	5/5	NM_001395362.2	P1
RTL4	ENST00000340433.4 linkuse as main transcript	c.179A>G	p.His60Arg	missense_variant	4/4		P1
RTL4	ENST00000695808.1 linkuse as main transcript	c.179A>G	p.His60Arg	missense_variant	3/3		P1

Frequencies

GnomAD3 genomes

AF:

0.000395

AC:

AN:

111297

Hom.:

Cov.:

AF XY:

0.000418

AC XY:

AN XY:

33497

show subpopulations

Gnomad AFR

AF:

0.00134

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000285

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000105

AC:

AN:

181535

Hom.:

AF XY:

0.000136

AC XY:

AN XY:

66299

show subpopulations

Gnomad AFR exome

AF:

0.00122

Gnomad AMR exome

AF:

0.0000732

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:

0.00

Gnomad OTH exome

AF:

0.000223

GnomAD4 exome

AF:

0.0000228

AC:

AN:

1097110

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

362546

show subpopulations

Gnomad4 AFR exome

AF:

0.000720

Gnomad4 AMR exome

AF:

0.0000284

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:

0.00000357

Gnomad4 OTH exome

AF:

0.0000434

GnomAD4 genome

AF:

0.000395

AC:

AN:

111353

Hom.:

Cov.:

AF XY:

0.000417

AC XY:

AN XY:

33563

show subpopulations

Gnomad4 AFR

AF:

0.00134

Gnomad4 AMR

AF:

0.000285

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000433

Hom.:

Bravo

AF:

0.000442

ESP6500AA

AF:

0.00183

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000165

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 14, 2022

The c.179A>G (p.H60R) alteration is located in exon 3 (coding exon 1) of the ZCCHC16 gene. This alteration results from a A to G substitution at nucleotide position 179, causing the histidine (H) at amino acid position 60 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

-0.54

BayesDel_noAF

Benign

-0.55

Cadd

Benign

Dann

Benign

0.92

DEOGEN2

Benign

0.031

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.45

M_CAP

Benign

0.012

MetaRNN

Benign

0.012

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

PrimateAI

Benign

0.32

PROVEAN

Benign

-2.1

REVEL

Benign

0.081

Sift

Uncertain

0.016

Sift4G

Pathogenic

0.0

Polyphen

0.81

Vest4

0.12

MVP

0.061

MPC

0.066

ClinPred

0.048

GERP RS

2.9

Varity_R

0.15

gMVP

0.053

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