chr7-92528883-C-T

Position:

• chr7-92528883-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001363367.1(RBM48):​c.-620C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RBM48 NM_001363367.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.59

Genes affected

RBM48 (HGNC:21785): (RNA binding motif protein 48) Predicted to enable RNA binding activity. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBM48	NM_032120.4	c.70C>T	p.Arg24Trp	missense_variant	1/5	ENST00000265732.10	NP_115496.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBM48	ENST00000265732.10	c.70C>T	p.Arg24Trp	missense_variant	1/5	1	NM_032120.4	ENSP00000265732.5
RBM48	ENST00000481551.5	c.70C>T	p.Arg24Trp	missense_variant	1/4	1		ENSP00000419242.1
RBM48	ENST00000496410	c.-364C>T		5_prime_UTR_premature_start_codon_gain_variant	1/3	3		ENSP00000418333.1
RBM48	ENST00000496410	c.-364C>T		5_prime_UTR_variant	1/3	3		ENSP00000418333.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 05, 2022

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 24 of the RBM48 protein (p.Arg24Trp). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). ClinVar contains an entry for this variant (Variation ID: 1435189). This variant has not been reported in the literature in individuals affected with RBM48-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T;.
Eigen	Benign	0.18
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.85	T;T
M_CAP	Benign	0.080	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	2.0	M;M
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-6.5	D;D
REVEL	Benign	0.28
Sift	Uncertain	0.022	D;D
Sift4G	Benign	0.068	T;T
Polyphen		0.97	D;.
Vest4		0.91
MutPred		0.74		Loss of disorder (P = 0.0107);Loss of disorder (P = 0.0107);
MVP		0.86
MPC		0.34
ClinPred		0.99	D
GERP RS		2.9
Varity_R		0.70
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs868085721; hg19: chr7-92158197;