1-230997119-A-C

Position:

• chr1-230997119-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_022786.3(ARV1):​c.674-2A>C variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARV1 NM_022786.3 splice_acceptor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.32

Genes affected

ARV1 (HGNC:29561): (ARV1 homolog, fatty acid homeostasis modulator) this gene encodes a transmembrane protein that contains a conserved zinc ribbon motif at the N- terminus. A similar protein in mouse is thought to function in fatty acid homeostasis. Mutations in this gene are associated with early infantile epileptic encephalopathy 38. [provided by RefSeq, Nov 2016]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.17892157 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARV1	NM_022786.3	c.674-2A>C		splice_acceptor_variant		ENST00000310256.7	NP_073623.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARV1	ENST00000310256.7	c.674-2A>C		splice_acceptor_variant		1	NM_022786.3	ENSP00000312458	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	26
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D;D
GERP RS		4.4

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.92
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.99		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1192627743; hg19: chr1-231132865;