1-230990117-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_022786.3(ARV1):c.302G>A(p.Gly101Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00657 in 1,603,664 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0041 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0068 (63 hom.)
• Consequence: ARV1 NM_022786.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.58

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 Benign. Variant got -16 ACMG points.

• BP6: Variant 1-230990117-G-A is Benign according to our data. Variant chr1-230990117-G-A is described in ClinVar as [Benign]. Clinvar id is 789436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00412 (627/152326) while in subpopulation SAS AF= 0.0195 (94/4828). AF 95% confidence interval is 0.0163. There are 4 homozygotes in gnomad4. There are 294 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARV1	NM_022786.3	c.302G>A	p.Gly101Glu	missense_variant	3/6	ENST00000310256.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARV1	ENST00000310256.7	c.302G>A	p.Gly101Glu	missense_variant	3/6	1	NM_022786.3	P1

Frequencies

GnomAD3 genomes AF: 0.00414 AC: 630 AN: 152208 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0201

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00607

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00565 AC: 1359 AN: 240508 Hom.: 7 AF XY: 0.00677 AC XY: 881 AN XY: 130210

Gnomad AFR exome AF: 0.00113

Gnomad AMR exome AF: 0.00175

Gnomad ASJ exome AF: 0.00513

Gnomad EAS exome AF: 0.0000564

Gnomad SAS exome AF: 0.0207

Gnomad FIN exome AF: 0.000279

Gnomad NFE exome AF: 0.00557

Gnomad OTH exome AF: 0.00616

GnomAD4 exome AF: 0.00682 AC: 9903 AN: 1451338 Hom.: 63 Cov.: 31 AF XY: 0.00721 AC XY: 5202 AN XY: 721824

Gnomad4 AFR exome AF: 0.00122

Gnomad4 AMR exome AF: 0.00196

Gnomad4 ASJ exome AF: 0.00498

Gnomad4 EAS exome AF: 0.0000762

Gnomad4 SAS exome AF: 0.0203

Gnomad4 FIN exome AF: 0.000375

Gnomad4 NFE exome AF: 0.00661

Gnomad4 OTH exome AF: 0.00887

GnomAD4 genome AF: 0.00412 AC: 627 AN: 152326 Hom.: 4 Cov.: 33 AF XY: 0.00395 AC XY: 294 AN XY: 74470

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0195

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00607

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00569 Hom.: 4

Bravo AF: 0.00422

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00663 AC: 57

ExAC AF: 0.00562 AC: 683

Asia WGS AF: 0.00866 AC: 33 AN: 3478

EpiCase AF: 0.00705

EpiControl AF: 0.00593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

ARV1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.19
Cadd	Pathogenic	30
Dann	Uncertain	1.0
DEOGEN2	Benign	0.13	T;T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D
MetaRNN	Benign	0.013	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.26
Sift	Benign	0.38	T;T
Sift4G	Benign	0.82	T;T
Polyphen		1.0	D;.
Vest4		0.84
MVP		0.90
MPC		0.78
ClinPred		0.017	T
GERP RS		6.2
Varity_R		0.60
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.30		Position offset: 33
DS_AL_spliceai		0.21		Position offset: -7

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

Publications

LitVar

Other links and lift over

dbSNP: rs35764859; hg19: chr1-231125863;