1-113797581-C-T

Position:

• chr1-113797581-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP3 BP4

The NM_018364.5(RSBN1):​c.1159G>A​(p.Glu387Lys) variant causes a missense change. 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: RSBN1 NM_018364.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.23

Genes affected

RSBN1 (HGNC:25642): (round spermatid basic protein 1) Predicted to enable dioxygenase activity and metal ion binding activity. Predicted to be involved in chromatin organization. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Multiple lines of computational evidence support a deleterious effect 6: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, PrimateAI [when max_spliceai, M_CAP, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.39928845).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RSBN1	NM_018364.5	c.1159G>A	p.Glu387Lys	missense_variant	2/7	ENST00000261441.9
RSBN1	XM_017001518.3	c.1159G>A	p.Glu387Lys	missense_variant	2/3
RSBN1	NR_130896.2	n.1223G>A		non_coding_transcript_exon_variant	2/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RSBN1	ENST00000261441.9	c.1159G>A	p.Glu387Lys	missense_variant	2/7	2	NM_018364.5	P1
RSBN1	ENST00000612242.4	c.1159G>A	p.Glu387Lys	missense_variant	2/7	2		P1
RSBN1	ENST00000615321.1	c.1015G>A	p.Glu339Lys	missense_variant	2/7	2
RSBN1	ENST00000476412.5	c.1015G>A	p.Glu339Lys	missense_variant, NMD_transcript_variant	2/8	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Dec 14, 2022

The c.1159G>A (p.E387K) alteration is located in exon 2 (coding exon 2) of the RSBN1 gene. This alteration results from a G to A substitution at nucleotide position 1159, causing the glutamic acid (E) at amino acid position 387 to be replaced by a lysine (K). 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	0.94
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T;T;T;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.40	T;T;T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.3	M;M;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-2.6	D;.;.;.
REVEL	Uncertain	0.36
Sift	Uncertain	0.013	D;.;.;.
Sift4G	Benign	0.15	T;T;T;T
Polyphen		1.0	D;D;.;.
Vest4		0.55
MutPred		0.38		Gain of ubiquitination at E387 (P = 0.0109);Gain of ubiquitination at E387 (P = 0.0109);.;.;
MVP		0.18
MPC		2.3
ClinPred		0.92	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.38
gMVP		0.92

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

LitVar

Other links and lift over

dbSNP: rs1044903172; hg19: chr1-114340203;