chr7-128313222-G-A

Position:

• chr7-128313222-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_018077.3(RBM28):​c.2098C>T​(p.Gln700Ter) variant causes a stop gained 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: RBM28 NM_018077.3 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.14

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBM28	NM_018077.3	c.2098C>T	p.Gln700Ter	stop_gained	18/19	ENST00000223073.6
RBM28	NM_001166135.2	c.1675C>T	p.Gln559Ter	stop_gained	14/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBM28	ENST00000223073.6	c.2098C>T	p.Gln700Ter	stop_gained	18/19	1	NM_018077.3	P1
RBM28	ENST00000415472.6	c.1675C>T	p.Gln559Ter	stop_gained	14/15	2
RBM28	ENST00000481788.1	n.470C>T		non_coding_transcript_exon_variant	3/4	3
RBM28	ENST00000495327.1	n.261C>T		non_coding_transcript_exon_variant	2/2	2

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 specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 12, 2023

Variant summary: RBM28 c.2098C>T (p.Gln700X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay. Emergering evidence suggests biallelic loss-of-function or reduced-function variants in RBM28 cause autosomal recessve Alopecia, neurological defects and endocrinopathy syndrome (PMID: 18439547,27077951, 33941690): At-least three variants (one missense, one caonical splice site variant, and one indel affecting canonical splice site) have been reported in 6 patients from two unrelated families diagnosed with ANE syndrome. The variant was absent in 251494 control chromosomes. To our knowledge, no occurrence of c.2098C>T in individuals affected with ANE Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.78
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.84	D
MutationTaster	Benign	1.0	D;D
Vest4		0.30
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-127953275;