chr19-35633793-C-T

Variant names:

• chr19-35633793-C-T
• rs754225112
• NM_024321.5:c.791C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024321.5(RBM42):​c.791C>T​(p.Ala264Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000434 in 1,498,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000042 (0 hom.)
• Consequence: RBM42 NM_024321.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.53
• Publications: 1 publications found

Genes affected

RBM42 (HGNC:28117): (RNA binding motif protein 42) Enables RNA binding activity. Predicted to act upstream of or within negative regulation of mRNA splicing, via spliceosome. Predicted to be located in cytoplasm and nucleus. Predicted to be part of ribonucleoprotein complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.113553256).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBM42	NM_024321.5	c.791C>T	p.Ala264Val	missense_variant	Exon 7 of 10	ENST00000262633.9	NP_077297.2
RBM42	NM_001319113.2	c.704C>T	p.Ala235Val	missense_variant	Exon 6 of 9		NP_001306042.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBM42	ENST00000262633.9	c.791C>T	p.Ala264Val	missense_variant	Exon 7 of 10	1	NM_024321.5	ENSP00000262633.3

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152208 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000552 AC: 6 AN: 108674 AF XY: 0.0000504

Gnomad AFR exome AF: 0.000139

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000988

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000423 AC: 57 AN: 1346610 Hom.: 0 Cov.: 30 AF XY: 0.0000392 AC XY: 26 AN XY: 662700

African (AFR) AF: 0.000176 AC: 5 AN: 28376

American (AMR) AF: 0.00 AC: 0 AN: 26320

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20020

East Asian (EAS) AF: 0.00 AC: 0 AN: 34778

South Asian (SAS) AF: 0.00 AC: 0 AN: 69696

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42526

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5304

European-Non Finnish (NFE) AF: 0.0000470 AC: 50 AN: 1063972

Other (OTH) AF: 0.0000360 AC: 2 AN: 55618

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152208 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74352

African (AFR) AF: 0.000121 AC: 5 AN: 41468

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000831

ExAC AF: 0.0000508 AC: 6

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 07, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.791C>T (p.A264V) alteration is located in exon 7 (coding exon 7) of the RBM42 gene. This alteration results from a C to T substitution at nucleotide position 791, causing the alanine (A) at amino acid position 264 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	0.10
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.034	.;T;T;T;T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.85	D;D;D;D;D
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.11	T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.34	.;N;.;.;.
PhyloP100		1.5
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.63	.;N;.;.;.
REVEL	Benign	0.040
Sift	Uncertain	0.0020	.;D;.;.;.
Sift4G	Benign	0.21	T;T;T;T;T
Polyphen		0.44	B;B;.;.;.
Vest4		0.46
MutPred		0.34		.;Gain of sheet (P = 0.0028);.;.;.;
MVP		0.19
MPC		0.28
ClinPred		0.064	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.11
gMVP		0.58
Mutation Taster		=87/13	polymorphism

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: rs754225112; hg19: chr19-36124695; COSMIC: COSV52897736; COSMIC: COSV52897736;