7-128330895-AAG-CCT

Variant names:

• chr7-128330895-AAG-CCT
• NM_018077.3:c.1051_1053delCTTinsAGG
• RBM28 p.Leu351Arg

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM5 PP3

The NM_018077.3(RBM28):​c.1051_1053delCTTinsAGG​(p.Leu351Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L351P) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: RBM28 NM_018077.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.06
• Publications: 0 publications found

Genes affected

RBM28 (HGNC:21863): (RNA binding motif protein 28) The protein encoded by this gene is a specific nucleolar component of the spliceosomal small nuclear ribonucleoprotein (snRNP)complexes . It specifically associates with U1, U2, U4, U5, and U6 small nuclear RNAs (snRNAs), possibly coordinating their transition through the nucleolus. Mutation in this gene causes alopecia, progressive neurological defects, and endocrinopathy (ANE syndrome), a pleiotropic and clinically heterogeneous disorder. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

RBM28 Gene-Disease associations (from GenCC):

• ANE syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-128330896-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 732.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018077.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBM28	NM_018077.3	MANE Select	c.1051_1053delCTTinsAGG	p.Leu351Arg	missense	N/A	NP_060547.2	A0A024R753
	RBM28	NM_001166135.2		c.628_630delCTTinsAGG	p.Leu210Arg	missense	N/A	NP_001159607.1	Q9NW13-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBM28	ENST00000223073.6	TSL:1 MANE Select	c.1051_1053delCTTinsAGG	p.Leu351Arg	missense	N/A	ENSP00000223073.1	Q9NW13-1
	RBM28	ENST00000899022.1		c.1117_1119delCTTinsAGG	p.Leu373Arg	missense	N/A	ENSP00000569080.1
	RBM28	ENST00000968249.1		c.1042_1044delCTTinsAGG	p.Leu348Arg	missense	N/A	ENSP00000638308.1

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.1

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr7-127970948;