4-154796763-A-T

Variant names:

• chr4-154796763-A-T
• rs1734372273
• NM_144979.5:c.11A>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_144979.5(RBM46):​c.11A>T​(p.Glu4Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000688 in 1,453,380 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RBM46 NM_144979.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.20

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14461574).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBM46	NM_144979.5	c.11A>T	p.Glu4Val	missense_variant	Exon 2 of 5	ENST00000281722.8	NP_659416.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBM46	ENST00000281722.8	c.11A>T	p.Glu4Val	missense_variant	Exon 2 of 5	1	NM_144979.5	ENSP00000281722.3
RBM46	ENST00000514866.5	c.11A>T	p.Glu4Val	missense_variant	Exon 2 of 6	2		ENSP00000424500.1
RBM46	ENST00000510397.5	c.11A>T	p.Glu4Val	missense_variant	Exon 2 of 5	2		ENSP00000422813.1
RBM46	ENST00000512640.1	c.11A>T	p.Glu4Val	missense_variant	Exon 2 of 3	4		ENSP00000426672.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453380 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 722868

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: 9.02e-7

Gnomad4 OTH exome AF: 0.00

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

Oct 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.11A>T (p.E4V) alteration is located in exon 2 (coding exon 1) of the RBM46 gene. This alteration results from a A to T substitution at nucleotide position 11, causing the glutamic acid (E) at amino acid position 4 to be replaced by a valine (V). 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	0.14
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.055	.;T;.;T
Eigen	Benign	0.020
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	T;T;T;T
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.14	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L;L;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.5	N;N;N;N
REVEL	Benign	0.11
Sift	Uncertain	0.0040	D;D;D;D
Sift4G	Benign	0.10	T;T;T;T
Polyphen		0.47	.;P;.;.
Vest4		0.34
MutPred		0.20		Loss of disorder (P = 0.0377);Loss of disorder (P = 0.0377);Loss of disorder (P = 0.0377);Loss of disorder (P = 0.0377);
MVP		0.36
MPC		1.8
ClinPred		0.83	D
GERP RS		5.6
Varity_R		0.21
gMVP		0.71

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: rs1734372273; hg19: chr4-155717915;