chr7-128313185-G-A

Position:

• chr7-128313185-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_018077.3(RBM28):​c.2135C>T​(p.Ser712Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00375 in 1,613,888 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (11 hom.)
• Consequence: RBM28 NM_018077.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.25

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0059055686).
• BP6: Variant 7-128313185-G-A is Benign according to our data. Variant chr7-128313185-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 788269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128313185-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBM28	NM_018077.3	c.2135C>T	p.Ser712Leu	missense_variant	18/19	ENST00000223073.6
RBM28	NM_001166135.2	c.1712C>T	p.Ser571Leu	missense_variant	14/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBM28	ENST00000223073.6	c.2135C>T	p.Ser712Leu	missense_variant	18/19	1	NM_018077.3	P1
RBM28	ENST00000415472.6	c.1712C>T	p.Ser571Leu	missense_variant	14/15	2
RBM28	ENST00000481788.1	n.507C>T		non_coding_transcript_exon_variant	3/4	3
RBM28	ENST00000495327.1	n.298C>T		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.00271 AC: 413 AN: 152152 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00294

Gnomad ASJ AF: 0.00864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00419

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00272 AC: 683 AN: 251492 Hom.: 3 AF XY: 0.00277 AC XY: 377 AN XY: 135920

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.00260

Gnomad ASJ exome AF: 0.00893

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00404

Gnomad OTH exome AF: 0.00358

GnomAD4 exome AF: 0.00386 AC: 5646 AN: 1461618 Hom.: 11 Cov.: 31 AF XY: 0.00370 AC XY: 2689 AN XY: 727142

Gnomad4 AFR exome AF: 0.000687

Gnomad4 AMR exome AF: 0.00250

Gnomad4 ASJ exome AF: 0.00922

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000232

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.00449

Gnomad4 OTH exome AF: 0.00384

GnomAD4 genome AF: 0.00271 AC: 413 AN: 152270 Hom.: 2 Cov.: 32 AF XY: 0.00216 AC XY: 161 AN XY: 74436

Gnomad4 AFR AF: 0.000842

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00419

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00438 Hom.: 3

Bravo AF: 0.00312

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00512 AC: 44

ExAC AF: 0.00233 AC: 283

Asia WGS AF: 0.000577 AC: 3 AN: 3478

EpiCase AF: 0.00387

EpiControl AF: 0.00516

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	RBM28: BP4, BS2 -

RBM28-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 11, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	21
DANN	Benign	0.90
DEOGEN2	Benign	0.0072	T;.
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.0059	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.9	N;N
REVEL	Benign	0.072
Sift	Benign	0.087	T;T
Sift4G	Benign	0.27	T;T
Polyphen		0.014	B;.
Vest4		0.23
MVP		0.20
MPC		0.13
ClinPred		0.021	T
GERP RS		4.3
Varity_R		0.046
gMVP		0.080

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

LitVar

Other links and lift over

dbSNP: rs73230638; hg19: chr7-127953238; COSMIC: COSV56161951;