X-112454897-T-C

Variant names:

• chrX-112454897-T-C
• rs1168469944
• NM_001395362.2:c.169T>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001395362.2(RTL4):​c.169T>C​(p.Ser57Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: RTL4 NM_001395362.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.838

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16967937).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTL4	NM_001395362.2	c.169T>C	p.Ser57Pro	missense_variant	Exon 5 of 5	ENST00000695839.1	NP_001382291.1
RTL4	NM_001004308.3	c.169T>C	p.Ser57Pro	missense_variant	Exon 3 of 3		NP_001004308.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RTL4	ENST00000695839.1	c.169T>C	p.Ser57Pro	missense_variant	Exon 5 of 5		NM_001395362.2	ENSP00000512211.1
RTL4	ENST00000340433.4	c.169T>C	p.Ser57Pro	missense_variant	Exon 4 of 4	6		ENSP00000340590.2
RTL4	ENST00000695808.1	c.169T>C	p.Ser57Pro	missense_variant	Exon 3 of 3			ENSP00000512188.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 22

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.169T>C (p.S57P) alteration is located in exon 3 (coding exon 1) of the ZCCHC16 gene. This alteration results from a T to C substitution at nucleotide position 169, causing the serine (S) at amino acid position 57 to be replaced by a proline (P). 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	0.081
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	12
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0044	T
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.99	T
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.61	N
REVEL	Benign	0.16
Sift	Benign	0.27	T
Sift4G	Benign	0.082	T
Polyphen		1.0	D
Vest4		0.20
MutPred		0.38		Loss of phosphorylation at Y56 (P = 0.079);
MVP		0.17
MPC		0.016
ClinPred		0.57	D
GERP RS		4.2
Varity_R		0.11
gMVP		0.39

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

Other links and lift over

dbSNP: rs1168469944; hg19: chrX-111698125; COSMIC: COSV61206883;