8-94372360-G-T

Variant summary

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

The NM_012415.3(RAD54B):c.2543C>A(p.Ser848Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: RAD54B NM_012415.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.954

Genes affected

RAD54B (HGNC:17228): (RAD54 homolog B) The protein encoded by this gene belongs to the DEAD-like helicase superfamily. It shares similarity with Saccharomyces cerevisiae RAD54 and RDH54, both of which are involved in homologous recombination and repair of DNA. This protein binds to double-stranded DNA, and displays ATPase activity in the presence of DNA. This gene is highly expressed in testis and spleen, which suggests active roles in meiotic and mitotic recombination. Homozygous mutations of this gene were observed in primary lymphoma and colon cancer. [provided by RefSeq, Jul 2008]

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=0.11388013).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD54B	NM_012415.3	c.2543C>A	p.Ser848Tyr	missense_variant	15/15	ENST00000336148.10
RAD54B	NM_001205263.2	c.1991C>A	p.Ser664Tyr	missense_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD54B	ENST00000336148.10	c.2543C>A	p.Ser848Tyr	missense_variant	15/15	1	NM_012415.3	P1
RAD54B	ENST00000519348.1	n.107C>A		non_coding_transcript_exon_variant	2/2	4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460972 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726798

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: 0.00000450

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Apr 04, 2023

The c.2543C>A (p.S848Y) alteration is located in exon 15 (coding exon 14) of the RAD54B gene. This alteration results from a C to A substitution at nucleotide position 2543, causing the serine (S) at amino acid position 848 to be replaced by a tyrosine (Y). 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	0.091
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	15
Dann	Benign	0.092
DEOGEN2	Benign	0.18	T;.
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.60	T;T
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.1	M;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-2.0	N;.
REVEL	Benign	0.092
Sift	Benign	0.43	T;.
Sift4G	Benign	0.18	T;T
Polyphen		0.0030	B;.
Vest4		0.15
MutPred		0.46		Loss of disorder (P = 8e-04);.;
MVP		0.31
MPC		0.11
ClinPred		0.065	T
GERP RS		-0.11
Varity_R		0.037
gMVP		0.35

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: chr8-95384588;