8-94378628-A-G

Position:

• chr8-94378628-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_012415.3(RAD54B):​c.2254T>C​(p.Ser752Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,452,494 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RAD54B NM_012415.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.13

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]

FSBP (HGNC:43653): (fibrinogen silencer binding protein) Enables identical protein binding activity. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.852

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD54B	NM_012415.3	c.2254T>C	p.Ser752Pro	missense_variant	13/15	ENST00000336148.10	NP_036547.1
RAD54B	NM_001205263.2	c.1702T>C	p.Ser568Pro	missense_variant	11/13		NP_001192192.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD54B	ENST00000336148.10	c.2254T>C	p.Ser752Pro	missense_variant	13/15	1	NM_012415.3	ENSP00000336606.5
FSBP	ENST00000517506.2	n.*1934T>C		non_coding_transcript_exon_variant	11/12	5		ENSP00000462684.1
FSBP	ENST00000517506.2	n.*1934T>C		3_prime_UTR_variant	11/12	5		ENSP00000462684.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1452494 Hom.: 0 Cov.: 29 AF XY: 0.00000277 AC XY: 2 AN XY: 722844

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: 0.00000181

Gnomad4 OTH exome AF: 0.00

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

Aug 26, 2022

The c.2254T>C (p.S752P) alteration is located in exon 13 (coding exon 12) of the RAD54B gene. This alteration results from a T to C substitution at nucleotide position 2254, causing the serine (S) at amino acid position 752 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	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.088	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Uncertain	2.5	M;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.4	N;.
REVEL	Uncertain	0.60
Sift	Uncertain	0.0060	D;.
Sift4G	Uncertain	0.0080	D;D
Polyphen		0.91	P;.
Vest4		0.70
MutPred		0.73		Loss of MoRF binding (P = 0.0593);.;
MVP		0.92
MPC		0.41
ClinPred		0.96	D
GERP RS		2.0
Varity_R		0.60
gMVP		0.87

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: chr8-95390856;