Genetic Variant RTL4:p.His219Arg (chrX-112455384-A-G) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_001395362.2(RTL4):c.656A>G(p.His219Arg) 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 1,098,155 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H219Y) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 9.1e-7 ( 0 hom. 1 hem. )

Consequence

RTL4
NM_001395362.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.57

Publications

0 publications found

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 was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.026111335).

BP6

Variant X-112455384-A-G is Benign according to our data. Variant chrX-112455384-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3156910.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001395362.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTL4	NM_001395362.2	MANE Select	c.656A>G	p.His219Arg	missense	Exon 5 of 5	NP_001382291.1	Q6ZR62
	RTL4	NM_001004308.3		c.656A>G	p.His219Arg	missense	Exon 3 of 3	NP_001004308.2	Q6ZR62

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RTL4	ENST00000695839.1	MANE Select	c.656A>G	p.His219Arg	missense	Exon 5 of 5	ENSP00000512211.1	Q6ZR62
RTL4	ENST00000340433.4	TSL:6	c.656A>G	p.His219Arg	missense	Exon 4 of 4	ENSP00000340590.2	Q6ZR62
RTL4	ENST00000695808.1		c.656A>G	p.His219Arg	missense	Exon 3 of 3	ENSP00000512188.1	Q6ZR62

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.11e-7

AC:

AN:

1098155

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

363535

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26400

American (AMR)

AF:

0.00

AC:

AN:

35206

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19377

East Asian (EAS)

AF:

0.00

AC:

AN:

30195

South Asian (SAS)

AF:

0.00

AC:

AN:

54123

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40526

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

842097

Other (OTH)

AF:

0.00

AC:

AN:

46096

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-1.1

CADD

Benign

0.035

(source)

DANN

Benign

0.21

DEOGEN2

Benign

0.0033

FATHMM_MKL

Benign

0.0030

LIST_S2

Benign

0.33

M_CAP

Benign

0.0039

MetaRNN

Benign

0.026

MetaSVM

Benign

-1.0

PhyloP100

-1.6

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.23

REVEL

Benign

0.010

Sift

Benign

0.43

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.051

MutPred

0.20

Gain of solvent accessibility (P = 0.1319)

MVP

0.17

MPC

0.013

ClinPred

0.030

GERP RS

-2.0

Varity_R

0.043

gMVP

0.44

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over