NM_015106.4:c.4232G>A

Variant names:

• chr3-51663248-G-A
• rs771221945
• NM_015106.4:c.4232G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_015106.4(RAD54L2):​c.4232G>A​(p.Arg1411Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000868 in 1,613,756 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. R1411W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: RAD54L2 NM_015106.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.70
• Publications: 1 publications found

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

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.207519).
• BS2: High AC in GnomAdExome4 at 10 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015106.4. 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
	RAD54L2	NM_015106.4	MANE Select	c.4232G>A	p.Arg1411Gln	missense	Exon 23 of 23	NP_055921.2	Q9Y4B4
	RAD54L2	NM_001322253.2		c.4232G>A	p.Arg1411Gln	missense	Exon 24 of 24	NP_001309182.1	Q9Y4B4
	RAD54L2	NM_001322256.2		c.4232G>A	p.Arg1411Gln	missense	Exon 22 of 22	NP_001309185.1	Q9Y4B4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD54L2	ENST00000684192.1	MANE Select	c.4232G>A	p.Arg1411Gln	missense	Exon 23 of 23	ENSP00000507587.1	Q9Y4B4
	RAD54L2	ENST00000409535.6	TSL:5	c.4232G>A	p.Arg1411Gln	missense	Exon 22 of 22	ENSP00000386520.1	Q9Y4B4
	RAD54L2	ENST00000871491.1		c.4232G>A	p.Arg1411Gln	missense	Exon 22 of 22	ENSP00000541550.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152044 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000967

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251168 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461712 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727138

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111870

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152044 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74270

African (AFR) AF: 0.0000967 AC: 4 AN: 41378

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000386 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.059	T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.21	T
MetaSVM	Uncertain	0.11	D
MutationAssessor	Benign	1.4	L
PhyloP100		2.7
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.27
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.63	T
Polyphen		0.95	P
Vest4		0.27
MVP		0.47
MPC		0.38
ClinPred		0.34	T
GERP RS		5.6
Varity_R		0.11
gMVP		0.27
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs771221945; hg19: chr3-51697264;