8-94399540-C-G

Variant names:

• chr8-94399540-C-G
• rs119490107
• NM_012415.3:c.1252G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM5

The NM_012415.3(RAD54B):​c.1252G>C​(p.Asp418His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D418Y) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAD54B NM_012415.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.71
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-94399540-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 5639.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD54B	NM_012415.3	c.1252G>C	p.Asp418His	missense_variant	Exon 8 of 15	ENST00000336148.10	NP_036547.1
RAD54B	NM_001205263.2	c.700G>C	p.Asp234His	missense_variant	Exon 6 of 13		NP_001192192.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD54B	ENST00000336148.10	c.1252G>C	p.Asp418His	missense_variant	Exon 8 of 15	1	NM_012415.3	ENSP00000336606.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Uncertain	0.60	D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Benign	1.1	L;.
PhyloP100		7.7
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.9	D;.
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0060	D;.
Sift4G	Uncertain	0.017	D;D
Polyphen		0.99	D;.
Vest4		0.39
MutPred		0.55		Loss of stability (P = 0.1887);.;
MVP		0.98
MPC		0.49
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.63
gMVP		0.58
Mutation Taster		=36/64	disease causing

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: rs119490107; hg19: chr8-95411768;