NM_022786.3:c.294+1G>A

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate

The NM_022786.3(ARV1):c.294+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000059 in 1,526,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000058 ( 0 hom. )

Consequence

ARV1
NM_022786.3 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 9.56

Publications

2 publications found

Variant links:

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]

ARV1 Gene-Disease associations (from GenCC):

developmental and epileptic encephalopathy, 38
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ARV1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.14705883 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-230988440-G-A is Pathogenic according to our data. Variant chr1-230988440-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 224496.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022786.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
ARV1	NM_022786.3	MANE Select	c.294+1G>A	splice_donor intron	N/A	NP_073623.1
ARV1	NM_001346992.2		c.294+1G>A	splice_donor intron	N/A	NP_001333921.1
ARV1	NR_144538.2		n.306+1G>A	splice_donor intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
ARV1	ENST00000310256.7	TSL:1 MANE Select	c.294+1G>A	splice_donor intron	N/A	ENSP00000312458.2
ARV1	ENST00000435927.5	TSL:3	c.252+1G>A	splice_donor intron	N/A	ENSP00000394547.1
ARV1	ENST00000450711.5	TSL:3	c.282+1G>A	splice_donor intron	N/A	ENSP00000416039.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00000953

AC:

AN:

209808

AF XY:

0.00000876

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000115

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000983

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000582

AC:

AN:

1374516

Hom.:

Cov.:

AF XY:

0.00000587

AC XY:

AN XY:

681960

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

30006

American (AMR)

AF:

0.00

AC:

AN:

33158

Ashkenazi Jewish (ASJ)

AF:

0.0000416

AC:

AN:

24064

East Asian (EAS)

AF:

0.00

AC:

AN:

36782

South Asian (SAS)

AF:

0.00

AC:

AN:

70800

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51434

Middle Eastern (MID)

AF:

0.000184

AC:

AN:

5444

European-Non Finnish (NFE)

AF:

0.00000469

AC:

AN:

1066126

Other (OTH)

AF:

0.0000176

AC:

AN:

56702

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000187107), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.381

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152126

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74316

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41420

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68012

Other (OTH)

AF:

0.000478

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000215

Hom.:

Bravo

AF:

0.00000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

ARV1-related disorder

Pathogenic:1

Feb 13, 2015

Department of Women and Children's Health, University of New South Wales

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Segregates with epileptic encephalopathy in family. Clinical phenotype consistent with previous patient reported with ARV1 related disorder.

Developmental and epileptic encephalopathy, 38

Pathogenic:1

Oct 23, 2020

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Uncertain

0.96

PhyloP100

9.6

GERP RS

5.7

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_DL_spliceai

1.0

Position offset: -1

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over