3-51663130-A-C

Position:

• chr3-51663130-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015106.4(RAD54L2):​c.4114A>C​(p.Asn1372His) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAD54L2 NM_015106.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.39

Genes affected

RAD54L2 (HGNC:29123): (RAD54 like 2) Predicted to enable ATP hydrolysis activity; protein kinase binding activity; and transcription coregulator activity. Predicted to be involved in DNA duplex unwinding. Predicted to act upstream of or within positive regulation of transcription by RNA polymerase II. Predicted to be located in nuclear speck. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

TEX264 (HGNC:30247): (testis expressed 264, ER-phagy receptor) Enables signaling receptor activity. Involved in protein-DNA covalent cross-linking repair. Acts upstream of or within reticulophagy. Located in several cellular components, including autophagosome membrane; endoplasmic reticulum membrane; and replication fork. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2777753).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD54L2	NM_015106.4	c.4114A>C	p.Asn1372His	missense_variant	23/23	ENST00000684192.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD54L2	ENST00000684192.1	c.4114A>C	p.Asn1372His	missense_variant	23/23		NM_015106.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 30, 2024

The c.4114A>C (p.N1372H) alteration is located in exon 22 (coding exon 21) of the RAD54L2 gene. This alteration results from a A to C substitution at nucleotide position 4114, causing the asparagine (N) at amino acid position 1372 to be replaced by a histidine (H). 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	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	0.71	D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.35	N
REVEL	Uncertain	0.35
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.036	D
Polyphen		0.99	D
Vest4		0.24
MutPred		0.15		Gain of catalytic residue at L1371 (P = 0.1463);
MVP		0.55
MPC		0.74
ClinPred		0.68	D
GERP RS		5.4
Varity_R		0.17
gMVP		0.60

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: chr3-51697146;