rs201779890

Variant names:

• chr1-145927328-C-G
• rs201779890
• NM_005105.5:c.67+32G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 8P and 6B. PP5_Very_Strong BP4 BS1_Supporting BS2

The NM_005105.5(RBM8A):​c.67+32G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00482 in 1,603,802 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic,low penetrance (★★).

• Frequency:
  • Genomes: 𝑓 0.0049 (5 hom., cov: 31)
  • Exomes 𝑓: 0.0048 (47 hom.)
• Consequence: RBM8A NM_005105.5 intron
• Clinical Significance: Pathogenic/Likely pathogenic/Pathogenic, low penetrance criteria provided, multiple submitters, no conflicts P:21 O:1
• Conservation: PhyloP100: 0.828
• Publications: 20 publications found

Genes affected

RBM8A (HGNC:9905): (RNA binding motif protein 8A) This gene encodes a protein with a conserved RNA-binding motif. The protein is found predominantly in the nucleus, although it is also present in the cytoplasm. It is preferentially associated with mRNAs produced by splicing, including both nuclear mRNAs and newly exported cytoplasmic mRNAs. It is thought that the protein remains associated with spliced mRNAs as a tag to indicate where introns had been present, thus coupling pre- and post-mRNA splicing events. Previously, it was thought that two genes encode this protein, RBM8A and RBM8B; it is now thought that the RBM8B locus is a pseudogene. There are two alternate translation start codons with this gene, which result in two forms of the protein. An allele mutation and a low-frequency noncoding single-nucleotide polymorphism (SNP) in this gene cause thrombocytopenia-absent radius (TAR) syndrome. [provided by RefSeq, Jul 2013]

ENSG00000280778 (HGNC:):

LIX1L-AS1 (HGNC:41210): (LIX1L antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PP5: Variant 1-145927328-C-G is Pathogenic according to our data. Variant chr1-145927328-C-G is described in ClinVar as Pathogenic/Likely_pathogenic/Pathogenic,_low_penetrance. ClinVar VariationId is 30465.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00489 (744/152258) while in subpopulation NFE AF = 0.00723 (492/68018). AF 95% confidence interval is 0.00671. There are 5 homozygotes in GnomAd4. There are 397 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005105.5. 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
	RBM8A	NM_005105.5	MANE Select	c.67+32G>C		intron	N/A	NP_005096.1	Q9Y5S9-1
	LIX1L-AS1	NR_147182.1		n.381C>G		non_coding_transcript_exon	Exon 2 of 3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBM8A	ENST00000583313.7	TSL:1 MANE Select	c.67+32G>C		intron	N/A	ENSP00000463058.2	Q9Y5S9-1
	RBM8A	ENST00000369307.4	TSL:1	c.67+32G>C		intron	N/A	ENSP00000358313.3	Q9Y5S9-2
	ENSG00000280778	ENST00000625258.1	TSL:5	c.-30+39C>G		intron	N/A	ENSP00000487094.1	A0A0D9SG24

Frequencies

GnomAD3 genomes AF: 0.00489 AC: 744 AN: 152140 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0182

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00723

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00547 AC: 1281 AN: 234162 AF XY: 0.00545

Gnomad AFR exome AF: 0.000480

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.000829

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0238

Gnomad NFE exome AF: 0.00671

Gnomad OTH exome AF: 0.00462

GnomAD4 exome AF: 0.00482 AC: 6994 AN: 1451544 Hom.: 47 Cov.: 31 AF XY: 0.00475 AC XY: 3422 AN XY: 720966

African (AFR) AF: 0.000600 AC: 20 AN: 33352

American (AMR) AF: 0.00126 AC: 54 AN: 42918

Ashkenazi Jewish (ASJ) AF: 0.00151 AC: 39 AN: 25876

East Asian (EAS) AF: 0.00 AC: 0 AN: 39410

South Asian (SAS) AF: 0.000495 AC: 42 AN: 84892

European-Finnish (FIN) AF: 0.0214 AC: 1131 AN: 52882

Middle Eastern (MID) AF: 0.000522 AC: 3 AN: 5750

European-Non Finnish (NFE) AF: 0.00492 AC: 5447 AN: 1106412

Other (OTH) AF: 0.00430 AC: 258 AN: 60052

GnomAD4 genome AF: 0.00489 AC: 744 AN: 152258 Hom.: 5 Cov.: 31 AF XY: 0.00533 AC XY: 397 AN XY: 74438

African (AFR) AF: 0.000457 AC: 19 AN: 41548

American (AMR) AF: 0.00137 AC: 21 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4822

European-Finnish (FIN) AF: 0.0182 AC: 193 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00723 AC: 492 AN: 68018

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00639 Hom.: 2

Bravo AF: 0.00317

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic/Pathogenic, low penetrance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
11	-	-	Radial aplasia-thrombocytopenia syndrome (12)
8	-	-	not provided (8)
1	-	-	Global developmental delay;C1850049:Clinodactyly of the 5th finger;C4021085:Abnormal brain morphology (1)
1	-	-	RBM8A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	16
DANN	Benign	0.72
PhyloP100		0.83
PromoterAI		-0.013	Neutral

Splicing

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

Other links and lift over

dbSNP: rs201779890; hg19: chr1-145507765;