1-110339877-T-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_022768.5(RBM15):c.472T>G(p.Ser158Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000388 in 1,602,942 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00024 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00040 (0 hom.)
• Consequence: RBM15 NM_022768.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.13

Genes affected

RBM15 (HGNC:14959): (RNA binding motif protein 15) Members of the SPEN (Split-end) family of proteins, including RBM15, have repressor function in several signaling pathways and may bind to RNA through interaction with spliceosome components (Hiriart et al., 2005 [PubMed 16129689]).[supplied by OMIM, Feb 2009]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.023350924).
• BS2: High AC in GnomAd at 36 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBM15	NM_022768.5	c.472T>G	p.Ser158Ala	missense_variant	1/3	ENST00000369784.9
RBM15	NM_001201545.2	c.472T>G	p.Ser158Ala	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBM15	ENST00000369784.9	c.472T>G	p.Ser158Ala	missense_variant	1/3	1	NM_022768.5	A2

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152028 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000456

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000186 AC: 46 AN: 247656 Hom.: 0 AF XY: 0.000201 AC XY: 27 AN XY: 134430

Gnomad AFR exome AF: 0.0000641

Gnomad AMR exome AF: 0.000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000330

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000304

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000404 AC: 586 AN: 1450794 Hom.: 0 Cov.: 37 AF XY: 0.000388 AC XY: 279 AN XY: 719522

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.000293

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000495

Gnomad4 OTH exome AF: 0.000401

GnomAD4 genome AF: 0.000237 AC: 36 AN: 152148 Hom.: 1 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74394

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000358 Hom.: 1

Bravo AF: 0.000261

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ExAC AF: 0.000189 AC: 23

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

Feb 15, 2023

The c.472T>G (p.S158A) alteration is located in exon 1 (coding exon 1) of the RBM15 gene. This alteration results from a T to G substitution at nucleotide position 472, causing the serine (S) at amino acid position 158 to be replaced by an alanine (A). 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	0.063
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	21
Dann	Benign	0.85
DEOGEN2	Benign	0.20	T;.;.;T;.
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.83	D
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.023	T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.55	N;N;N;N;.
MutationTaster	Benign	0.97	N
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.12	N;.;.;.;.
REVEL	Benign	0.013
Sift	Benign	0.21	T;.;.;.;.
Sift4G	Benign	0.85	T;T;T;T;T
Polyphen		0.023	B;.;B;B;.
Vest4		0.12
MVP		0.41
MPC		0.60
ClinPred		0.034	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9
Varity_R		0.12
gMVP		0.21

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: rs200933258; hg19: chr1-110882499;