X-112455384-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_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. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: RTL4 NM_001395362.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.57

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]

ACMG classification

Verdict is Likely_benign. Variant got -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 id is 3156910.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RTL4	NM_001395362.2	c.656A>G	p.His219Arg	missense_variant	5/5	ENST00000695839.1
RTL4	NM_001004308.3	c.656A>G	p.His219Arg	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RTL4	ENST00000695839.1	c.656A>G	p.His219Arg	missense_variant	5/5		NM_001395362.2	P1
RTL4	ENST00000340433.4	c.656A>G	p.His219Arg	missense_variant	4/4			P1
RTL4	ENST00000695808.1	c.656A>G	p.His219Arg	missense_variant	3/3			P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1098155 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 1 AN XY: 363535

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: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 10, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-1.1
Cadd	Benign	0.035
Dann	Benign	0.21
DEOGEN2	Benign	0.0033	T
FATHMM_MKL	Benign	0.0030	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.026	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.010
Sift	Benign	0.43	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.051
MutPred		0.20		Gain of solvent accessibility (P = 0.1319);
MVP		0.17
MPC		0.013
ClinPred		0.030	T
GERP RS		-2.0
Varity_R		0.043
gMVP		0.44

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-111698612;