chr7-128313243-G-A

Position:

• chr7-128313243-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.2077C>T​(p.His693Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00301 in 1,614,124 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 0.0020 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (11 hom.)
• Consequence: RBM28 NM_018077.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.54

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=0.0071209073).
• BP6: Variant 7-128313243-G-A is Benign according to our data. Variant chr7-128313243-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 774195.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128313243-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.2077C>T	p.His693Tyr	missense_variant	18/19	ENST00000223073.6
RBM28	NM_001166135.2	c.1654C>T	p.His552Tyr	missense_variant	14/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBM28	ENST00000223073.6	c.2077C>T	p.His693Tyr	missense_variant	18/19	1	NM_018077.3	P1
RBM28	ENST00000415472.6	c.1654C>T	p.His552Tyr	missense_variant	14/15	2
RBM28	ENST00000481788.1	n.449C>T		non_coding_transcript_exon_variant	3/4	3
RBM28	ENST00000495327.1	n.240C>T		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.00204 AC: 311 AN: 152140 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00208

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00360

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00208 AC: 524 AN: 251494 Hom.: 2 AF XY: 0.00217 AC XY: 295 AN XY: 135922

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00211

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00216

Gnomad FIN exome AF: 0.000554

Gnomad NFE exome AF: 0.00307

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00311 AC: 4540 AN: 1461866 Hom.: 11 Cov.: 31 AF XY: 0.00303 AC XY: 2201 AN XY: 727232

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.00192

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00187

Gnomad4 FIN exome AF: 0.000693

Gnomad4 NFE exome AF: 0.00363

Gnomad4 OTH exome AF: 0.00303

GnomAD4 genome AF: 0.00204 AC: 311 AN: 152258 Hom.: 2 Cov.: 32 AF XY: 0.00181 AC XY: 135 AN XY: 74432

Gnomad4 AFR AF: 0.000650

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00208

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00360

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00294 Hom.: 2

Bravo AF: 0.00208

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00302 AC: 26

ExAC AF: 0.00222 AC: 269

EpiCase AF: 0.00349

EpiControl AF: 0.00332

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	RBM28: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

RBM28-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 19, 2023

This variant is classified as likely 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	-0.59	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0042	T;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.0071	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;.
MutationTaster	Benign	0.85	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.074
Sift	Benign	0.12	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.48	P;.
Vest4		0.30
MVP		0.24
MPC		0.18
ClinPred		0.012	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.059
gMVP		0.077

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: rs142674151; hg19: chr7-127953296; COSMIC: COSV99776026;