chr19-35632966-G-A

Variant names:

• chr19-35632966-G-A
• rs78375138
• NM_024321.5:c.473G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM1 BP4_Strong

The NM_024321.5(RBM42):​c.473G>A​(p.Arg158His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000071 in 1,606,252 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: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000065 (0 hom.)
• Consequence: RBM42 NM_024321.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.13
• Publications: 2 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: Likely_benign. The variant received -2 ACMG points.

• PM1: In a modified_residue Asymmetric dimethylarginine (size 0) in uniprot entity RBM42_HUMAN
• BP4: Computational evidence support a benign effect (MetaRNN=0.037353784).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBM42	NM_024321.5	c.473G>A	p.Arg158His	missense_variant	Exon 5 of 10	ENST00000262633.9	NP_077297.2
RBM42	NM_001319113.2	c.443-132G>A		intron_variant	Intron 4 of 8		NP_001306042.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBM42	ENST00000262633.9	c.473G>A	p.Arg158His	missense_variant	Exon 5 of 10	1	NM_024321.5	ENSP00000262633.3

Frequencies

GnomAD3 genomes AF: 0.000126 AC: 19 AN: 151362 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000341

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000737

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000684 AC: 17 AN: 248628 AF XY: 0.0000669

Gnomad AFR exome AF: 0.000619

Gnomad AMR exome AF: 0.0000294

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000445

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000653 AC: 95 AN: 1454772 Hom.: 0 Cov.: 31 AF XY: 0.0000718 AC XY: 52 AN XY: 723862

African (AFR) AF: 0.000752 AC: 25 AN: 33262

American (AMR) AF: 0.0000678 AC: 3 AN: 44244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25924

East Asian (EAS) AF: 0.00 AC: 0 AN: 39464

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85886

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.0000560 AC: 62 AN: 1106804

Other (OTH) AF: 0.0000666 AC: 4 AN: 60078

GnomAD4 genome AF: 0.000125 AC: 19 AN: 151480 Hom.: 0 Cov.: 32 AF XY: 0.000122 AC XY: 9 AN XY: 73982

African (AFR) AF: 0.000340 AC: 14 AN: 41206

American (AMR) AF: 0.00 AC: 0 AN: 15242

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10490

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000737 AC: 5 AN: 67846

Other (OTH) AF: 0.00 AC: 0 AN: 2098

Alfa AF: 0.000178 Hom.: 0

Bravo AF: 0.000140

ExAC AF: 0.0000906 AC: 11

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 18, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.473G>A (p.R158H) alteration is located in exon 5 (coding exon 5) of the RBM42 gene. This alteration results from a G to A substitution at nucleotide position 473, causing the arginine (R) at amino acid position 158 to be replaced by a histidine (H). 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	Pathogenic	0.80
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.055
Eigen_PC	Benign	0.10
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.037	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		3.1
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.13
Sift	Uncertain	0.028	D
Sift4G	Benign	0.16	T
Polyphen		0.0	B
Vest4		0.30
MVP		0.15
MPC		0.97
ClinPred		0.11	T
GERP RS		4.2
Varity_R		0.12
gMVP		0.19
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs78375138; hg19: chr19-36123868; COSMIC: COSV99386921; COSMIC: COSV99386921;