Genetic Variant NM_001395362.2:c.569A>T (chrX-112455297-A-T) – 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.569A>T(p.Asp190Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000423 in 1,209,871 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 150 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/19 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. D190H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., 7 hem., cov: 23)

Exomes 𝑓: 0.00045 ( 0 hom. 143 hem. )

Consequence

RTL4
NM_001395362.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.401

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=0.2001388).

BS2

High Hemizygotes in GnomAd4 at 7 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTL4	NM_001395362.2 link	c.569A>T	p.Asp190Val	missense_variant	Exon 5 of 5	ENST00000695839.1	NP_001382291.1
RTL4	NM_001004308.3 link	c.569A>T	p.Asp190Val	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.569A>T	p.Asp190Val	missense_variant	Exon 5 of 5		NM_001395362.2	ENSP00000512211.1	Q6ZR62
RTL4	ENST00000340433.4 link	c.569A>T	p.Asp190Val	missense_variant	Exon 4 of 4	6		ENSP00000340590.2	Q6ZR62
RTL4	ENST00000695808.1 link	c.569A>T	p.Asp190Val	missense_variant	Exon 3 of 3			ENSP00000512188.1	Q6ZR62

Frequencies

GnomAD3 genomes

AF:

0.000206

AC:

AN:

111774

Hom.:

Cov.:

AF XY:

0.000206

AC XY:

AN XY:

33920

show subpopulations

Gnomad AFR

AF:

0.0000977

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:

0.000376

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000203

AC:

AN:

182356

Hom.:

AF XY:

0.0000893

AC XY:

AN XY:

67172

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000256

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000125

Gnomad NFE exome

AF:

0.000321

Gnomad OTH exome

AF:

0.000443

GnomAD4 exome

AF:

0.000445

AC:

489

AN:

1098097

Hom.:

Cov.:

AF XY:

0.000393

AC XY:

143

AN XY:

363473

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000227

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000740

Gnomad4 NFE exome

AF:

0.000537

Gnomad4 OTH exome

AF:

0.000564

GnomAD4 genome

AF:

0.000206

AC:

AN:

111774

Hom.:

Cov.:

AF XY:

0.000206

AC XY:

AN XY:

33920

show subpopulations

Gnomad4 AFR

AF:

0.0000977

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:

0.000376

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000260

Hom.:

Bravo

AF:

0.000200

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000692

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.000140

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 01, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.569A>T (p.D190V) alteration is located in exon 3 (coding exon 1) of the ZCCHC16 gene. This alteration results from a A to T substitution at nucleotide position 569, causing the aspartic acid (D) at amino acid position 190 to be replaced by a valine (V). 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

0.089

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.16

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.46

M_CAP

Benign

0.0076

MetaRNN

Benign

0.20

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.31

PROVEAN

Pathogenic

-5.8

REVEL

Benign

0.12

Sift

Uncertain

0.0050

Sift4G

Pathogenic

0.0

Polyphen

0.98

Vest4

0.27

MVP

0.38

MPC

0.017

ClinPred

0.33

GERP RS

0.45

Varity_R

0.42

gMVP

0.57

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