19-10317746-C-A

Variant names:

• chr19-10317746-C-A
• rs377043925
• NM_133452.3:c.2017G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_133452.3(RAVER1):​c.2017G>T​(p.Gly673*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,441,584 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RAVER1 NM_133452.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.553
• Publications: 0 publications found

Genes affected

RAVER1 (HGNC:30296): (ribonucleoprotein, PTB binding 1) Enables RNA binding activity. Predicted to be involved in regulation of alternative mRNA splicing, via spliceosome. Predicted to be located in cytoplasm. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000267303 (HGNC:):

ACMG classification

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

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133452.3. 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
	RAVER1	NM_133452.3	MANE Select	c.2017G>T	p.Gly673*	stop_gained	Exon 12 of 13	NP_597709.3	A0A087WZ13
	RAVER1	NM_001366174.1		c.1942G>T	p.Gly648*	stop_gained	Exon 13 of 14	NP_001353103.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAVER1	ENST00000617231.5	TSL:5 MANE Select	c.2017G>T	p.Gly673*	stop_gained	Exon 12 of 13	ENSP00000482277.1	A0A087WZ13
	ENSG00000267303	ENST00000586529.1	TSL:5	n.271G>T		non_coding_transcript_exon	Exon 4 of 8	ENSP00000467814.1	K7EQG2
	RAVER1	ENST00000592208.5	TSL:1	n.3251G>T		non_coding_transcript_exon	Exon 9 of 10

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1441584 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 715870

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33140

American (AMR) AF: 0.00 AC: 0 AN: 42948

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25698

East Asian (EAS) AF: 0.0000256 AC: 1 AN: 39096

South Asian (SAS) AF: 0.00 AC: 0 AN: 83336

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50648

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4426

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1102736

Other (OTH) AF: 0.00 AC: 0 AN: 59556

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	34
DANN	Uncertain	0.98
Eigen	Uncertain	0.26
Eigen_PC	Benign	-0.030
FATHMM_MKL	Benign	0.54	D
PhyloP100		0.55
Vest4		0.17
GERP RS		0.56
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=27/173	disease causing (fs/PTC)

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

Other links and lift over

dbSNP: rs377043925; hg19: chr19-10428422;