19-10318372-T-C

Variant names:

• chr19-10318372-T-C
• rs1272752501
• NM_133452.3:c.1846A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_133452.3(RAVER1):​c.1846A>G​(p.Met616Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000314 in 1,594,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RAVER1 NM_133452.3 missense, splice_region
• Scores: Splicing: ADA: 0.00009948
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.81
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09753394).

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.1846A>G	p.Met616Val	missense splice_region	Exon 11 of 13	NP_597709.3	A0A087WZ13
	RAVER1	NM_001366174.1		c.1771A>G	p.Met591Val	missense splice_region	Exon 12 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.1846A>G	p.Met616Val	missense splice_region	Exon 11 of 13	ENSP00000482277.1	A0A087WZ13
	ENSG00000267303	ENST00000586529.1	TSL:5	n.100A>G		splice_region non_coding_transcript_exon	Exon 3 of 8	ENSP00000467814.1	K7EQG2
	RAVER1	ENST00000592208.5	TSL:1	n.3080A>G		splice_region non_coding_transcript_exon	Exon 8 of 10

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000450 AC: 1 AN: 222310 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000984

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1442638 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 717674

African (AFR) AF: 0.00 AC: 0 AN: 32248

American (AMR) AF: 0.00 AC: 0 AN: 40060

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25350

East Asian (EAS) AF: 0.00 AC: 0 AN: 38496

South Asian (SAS) AF: 0.00 AC: 0 AN: 84228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51770

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 9.05e-7 AC: 1 AN: 1105290

Other (OTH) AF: 0.00 AC: 0 AN: 59484

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74326

African (AFR) AF: 0.00 AC: 0 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	15
DANN	Benign	0.62
DEOGEN2	Benign	0.0039	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.098	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.8
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.21
Sift	Benign	0.84	T
Sift4G	Benign	0.56	T
Polyphen		0.010	B
Vest4		0.35
MutPred		0.19		Gain of methylation at K632 (P = 0.0405)
MVP		0.58
MPC		0.13
ClinPred		0.083	T
GERP RS		5.1
gMVP		0.32
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000099
dbscSNV1_RF	Benign	0.030
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: rs1272752501; hg19: chr19-10429048;