X-47145462-T-C

Position:

• chrX-47145462-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The ENST00000329236.8(RBM10):​c.16T>C​(p.Ser6Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0158 in 1,150,321 control chromosomes in the GnomAD database, including 1,800 homozygotes. There are 4,737 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 8/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.082 (949 hom., 2241 hem., cov: 22)
  • Exomes 𝑓: 0.0088 (851 hom. 2496 hem.)
• Consequence: RBM10 ENST00000329236.8 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.666

Genes affected

RBM10 (HGNC:9896): (RNA binding motif protein 10) This gene encodes a nuclear protein that belongs to a family proteins that contain an RNA-binding motif. The encoded protein associates with hnRNP proteins and may be involved in regulating alternative splicing. Defects in this gene are the cause of the X-linked recessive disorder, TARP syndrome. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Mar 2011]

NDUFB11 (HGNC:20372): (NADH:ubiquinone oxidoreductase subunit B11) The protein encoded by this gene is a subunit of the multisubunit NADH:ubiquinone oxidoreductase (complex I). Mammalian complex I is located at the mitochondrial inner membrane. This protein has NADH dehydrogenase activity and oxidoreductase activity. It transfers electrons from NADH to ubiquinone. Mutations in the human gene are associated with linear skin defects with multiple congenital anomalies 3 and mitochondrial complex I deficiency. [provided by RefSeq, Dec 2016]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RBM10. . Gene score misZ 4.4623 (greater than the threshold 3.09). GenCC has associacion of gene with TARP syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0011967719).
• BP6: Variant X-47145462-T-C is Benign according to our data. Variant chrX-47145462-T-C is described in ClinVar as [Benign]. Clinvar id is 1296132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-47145462-T-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.279 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBM10	NM_005676.5	c.-149T>C		5_prime_UTR_variant	1/24	ENST00000377604.8	NP_005667.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBM10	ENST00000377604.8	c.-149T>C		5_prime_UTR_variant	1/24	1	NM_005676.5	ENSP00000366829	A1

Frequencies

GnomAD3 genomes AF: 0.0817 AC: 8902 AN: 109000 Hom.: 943 Cov.: 22 AF XY: 0.0707 AC XY: 2219 AN XY: 31384

Gnomad AFR AF: 0.283

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0331

Gnomad ASJ AF: 0.00304

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000391

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0214

Gnomad NFE AF: 0.000991

Gnomad OTH AF: 0.0644

GnomAD3 exomes AF: 0.0181 AC: 1785 AN: 98378 Hom.: 163 AF XY: 0.0134 AC XY: 488 AN XY: 36306

Gnomad AFR exome AF: 0.281

Gnomad AMR exome AF: 0.0140

Gnomad ASJ exome AF: 0.00197

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000999

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000743

Gnomad OTH exome AF: 0.0104

GnomAD4 exome AF: 0.00884 AC: 9202 AN: 1041287 Hom.: 851 Cov.: 30 AF XY: 0.00733 AC XY: 2496 AN XY: 340447

Gnomad4 AFR exome AF: 0.292

Gnomad4 AMR exome AF: 0.0168

Gnomad4 ASJ exome AF: 0.00183

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00122

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000338

Gnomad4 OTH exome AF: 0.0232

GnomAD4 genome AF: 0.0820 AC: 8939 AN: 109034 Hom.: 949 Cov.: 22 AF XY: 0.0713 AC XY: 2241 AN XY: 31428

Gnomad4 AFR AF: 0.284

Gnomad4 AMR AF: 0.0331

Gnomad4 ASJ AF: 0.00304

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000393

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000991

Gnomad4 OTH AF: 0.0636

Alfa AF: 0.0415 Hom.: 265

Bravo AF: 0.0950

ExAC AF: 0.0117 AC: 240

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

RBM10-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 11, 2019

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
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	19
DANN	Benign	0.93
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.17	T
MetaRNN	Benign	0.0012	T
MutationTaster	Benign	1.3e-13	P;P;P;P
PrimateAI	Uncertain	0.61	T
Sift4G	Benign	0.29	T
Vest4		0.011
GERP RS		4.1
gMVP		0.052

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: rs5952419; hg19: chrX-47004861; COSMIC: COSV52102664; COSMIC: COSV52102664;