rs79167802

Positions:

• chr4-154798037-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000281722.8(RBM46):​c.378T>G​(p.Ile126Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0197 in 1,613,818 control chromosomes in the GnomAD database, including 751 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.018 (76 hom., cov: 32)
  • Exomes 𝑓: 0.020 (675 hom.)
• Consequence: RBM46 ENST00000281722.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.62

Genes affected

RBM46 (HGNC:28401): (RNA binding motif protein 46) Predicted to enable mRNA binding activity. Predicted to act upstream of or within mRNA stabilization and trophectodermal cell differentiation. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00208053).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBM46	NM_144979.5	c.378T>G	p.Ile126Met	missense_variant	3/5	ENST00000281722.8	NP_659416.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBM46	ENST00000281722.8	c.378T>G	p.Ile126Met	missense_variant	3/5	1	NM_144979.5	ENSP00000281722	A1
RBM46	ENST00000514866.5	c.378T>G	p.Ile126Met	missense_variant	3/6	2		ENSP00000424500	P4
RBM46	ENST00000510397.5	c.378T>G	p.Ile126Met	missense_variant	3/5	2		ENSP00000422813
RBM46	ENST00000512640.1	c.378T>G	p.Ile126Met	missense_variant	3/3	4		ENSP00000426672

Frequencies

GnomAD3 genomes AF: 0.0182 AC: 2769 AN: 152172 Hom.: 76 Cov.: 32

Gnomad AFR AF: 0.00362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0147

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.130

Gnomad SAS AF: 0.0207

Gnomad FIN AF: 0.0387

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0163

Gnomad OTH AF: 0.0177

GnomAD3 exomes AF: 0.0268 AC: 6734 AN: 251004 Hom.: 212 AF XY: 0.0268 AC XY: 3632 AN XY: 135700

Gnomad AFR exome AF: 0.00377

Gnomad AMR exome AF: 0.0198

Gnomad ASJ exome AF: 0.0173

Gnomad EAS exome AF: 0.137

Gnomad SAS exome AF: 0.0190

Gnomad FIN exome AF: 0.0348

Gnomad NFE exome AF: 0.0160

Gnomad OTH exome AF: 0.0251

GnomAD4 exome AF: 0.0199 AC: 29040 AN: 1461528 Hom.: 675 Cov.: 32 AF XY: 0.0200 AC XY: 14519 AN XY: 727030

Gnomad4 AFR exome AF: 0.00350

Gnomad4 AMR exome AF: 0.0197

Gnomad4 ASJ exome AF: 0.0167

Gnomad4 EAS exome AF: 0.147

Gnomad4 SAS exome AF: 0.0196

Gnomad4 FIN exome AF: 0.0340

Gnomad4 NFE exome AF: 0.0151

Gnomad4 OTH exome AF: 0.0216

GnomAD4 genome AF: 0.0182 AC: 2771 AN: 152290 Hom.: 76 Cov.: 32 AF XY: 0.0197 AC XY: 1468 AN XY: 74468

Gnomad4 AFR AF: 0.00361

Gnomad4 AMR AF: 0.0148

Gnomad4 ASJ AF: 0.0161

Gnomad4 EAS AF: 0.131

Gnomad4 SAS AF: 0.0207

Gnomad4 FIN AF: 0.0387

Gnomad4 NFE AF: 0.0163

Gnomad4 OTH AF: 0.0189

Alfa AF: 0.0199 Hom.: 120

Bravo AF: 0.0164

TwinsUK AF: 0.0108 AC: 40

ALSPAC AF: 0.0138 AC: 53

ESP6500AA AF: 0.00409 AC: 18

ESP6500EA AF: 0.0164 AC: 141

ExAC AF: 0.0256 AC: 3107

Asia WGS AF: 0.0620 AC: 216 AN: 3478

EpiCase AF: 0.0163

EpiControl AF: 0.0139

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	.;T;.;T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.89	D;D;D;D
MetaRNN	Benign	0.0021	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;M;M;.
MutationTaster	Benign	0.000024	P;P;P
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.9	D;D;D;D
REVEL	Benign	0.27
Sift	Uncertain	0.013	D;D;D;D
Sift4G	Uncertain	0.018	D;D;D;T
Polyphen		0.99	.;D;.;.
Vest4		0.52
MPC		2.3
ClinPred		0.036	T
GERP RS		2.1
Varity_R		0.41
gMVP		0.81

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: rs79167802; hg19: chr4-155719189; COSMIC: COSV55982301;