19-35633763-C-T

Variant names:

• chr19-35633763-C-T
• rs371819218
• NM_024321.5:c.761C>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.761C>T​(p.Ala254Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00007 in 1,485,314 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 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000074 (0 hom.)
• Consequence: RBM42 NM_024321.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.661
• Publications: 3 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=0.0905554).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBM42	NM_024321.5	c.761C>T	p.Ala254Val	missense_variant	Exon 7 of 10	ENST00000262633.9	NP_077297.2
RBM42	NM_001319113.2	c.674C>T	p.Ala225Val	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.761C>T	p.Ala254Val	missense_variant	Exon 7 of 10	1	NM_024321.5	ENSP00000262633.3

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000118 AC: 13 AN: 110266 AF XY: 0.000133

Gnomad AFR exome AF: 0.000140

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: 0.000174

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000735 AC: 98 AN: 1333098 Hom.: 0 Cov.: 31 AF XY: 0.0000657 AC XY: 43 AN XY: 654586

African (AFR) AF: 0.0000734 AC: 2 AN: 27250

American (AMR) AF: 0.00 AC: 0 AN: 24988

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19236

East Asian (EAS) AF: 0.0000594 AC: 2 AN: 33648

South Asian (SAS) AF: 0.0000598 AC: 4 AN: 66922

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45760

Middle Eastern (MID) AF: 0.000190 AC: 1 AN: 5260

European-Non Finnish (NFE) AF: 0.0000805 AC: 85 AN: 1055302

Other (OTH) AF: 0.0000731 AC: 4 AN: 54732

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152216 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74364

African (AFR) AF: 0.00 AC: 0 AN: 41464

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5194

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68032

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

Alfa AF: 0.000310 Hom.: 0

Bravo AF: 0.0000453

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000351 AC: 3

ExAC AF: 0.0000589 AC: 7

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.761C>T (p.A254V) 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 761, causing the alanine (A) at amino acid position 254 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	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.068	.;T;T;T;T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.85	D;D;D;D;D
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.091	T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	.;N;.;.;.
PhyloP100		0.66
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.4	.;N;.;.;.
REVEL	Benign	0.086
Sift	Uncertain	0.0090	.;D;.;.;.
Sift4G	Benign	0.25	T;T;T;T;T
Polyphen		0.016	B;B;.;.;.
Vest4		0.37
MVP		0.25
MPC		0.28
ClinPred		0.048	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.062
gMVP		0.40
Mutation Taster		=91/9	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: rs371819218; hg19: chr19-36124665; COSMIC: COSV52897367; COSMIC: COSV52897367;