1-230979169-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_022786.3(ARV1):c.64A>T(p.Thr22Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00274 in 1,611,858 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (7 hom.)
• Consequence: ARV1 NM_022786.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.159

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004591197).
• BP6: Variant 1-230979169-A-T is Benign according to our data. Variant chr1-230979169-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 777986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-230979169-A-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00193 (293/151628) while in subpopulation SAS AF= 0.00376 (18/4792). AF 95% confidence interval is 0.00246. There are 1 homozygotes in gnomad4. There are 149 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARV1	NM_022786.3	c.64A>T	p.Thr22Ser	missense_variant	1/6	ENST00000310256.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARV1	ENST00000310256.7	c.64A>T	p.Thr22Ser	missense_variant	1/6	1	NM_022786.3	P1

Frequencies

GnomAD3 genomes AF: 0.00194 AC: 294 AN: 151510 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000461

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00375

Gnomad FIN AF: 0.00398

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00280

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00203 AC: 506 AN: 249286 Hom.: 3 AF XY: 0.00228 AC XY: 307 AN XY: 134830

Gnomad AFR exome AF: 0.000497

Gnomad AMR exome AF: 0.000996

Gnomad ASJ exome AF: 0.000299

Gnomad EAS exome AF: 0.000110

Gnomad SAS exome AF: 0.00289

Gnomad FIN exome AF: 0.00323

Gnomad NFE exome AF: 0.00253

Gnomad OTH exome AF: 0.00264

GnomAD4 exome AF: 0.00282 AC: 4116 AN: 1460230 Hom.: 7 Cov.: 31 AF XY: 0.00275 AC XY: 1997 AN XY: 726378

Gnomad4 AFR exome AF: 0.000419

Gnomad4 AMR exome AF: 0.000942

Gnomad4 ASJ exome AF: 0.000384

Gnomad4 EAS exome AF: 0.0000506

Gnomad4 SAS exome AF: 0.00322

Gnomad4 FIN exome AF: 0.00331

Gnomad4 NFE exome AF: 0.00305

Gnomad4 OTH exome AF: 0.00327

GnomAD4 genome AF: 0.00193 AC: 293 AN: 151628 Hom.: 1 Cov.: 32 AF XY: 0.00201 AC XY: 149 AN XY: 74106

Gnomad4 AFR AF: 0.000460

Gnomad4 AMR AF: 0.00151

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.00376

Gnomad4 FIN AF: 0.00398

Gnomad4 NFE AF: 0.00279

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00248 Hom.: 0

Bravo AF: 0.00163

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00198 AC: 17

ExAC AF: 0.00182 AC: 221

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00327

EpiControl AF: 0.00262

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	ARV1: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 12, 2020

- -

ARV1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 24, 2020

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	9.5
Dann	Benign	0.81
DEOGEN2	Benign	0.096	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.47	T;T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.0046	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.14	N;N
REVEL	Benign	0.0070
Sift	Benign	0.28	T;T
Sift4G	Benign	0.34	T;T
Polyphen		0.0010	B;.
Vest4		0.20
MutPred		0.14		Gain of disorder (P = 0.0426);Gain of disorder (P = 0.0426);
MVP		0.37
MPC		0.15
ClinPred		0.0016	T
GERP RS		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.040
gMVP		0.30

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

Publications

LitVar

Other links and lift over

dbSNP: rs143532693; hg19: chr1-231114915; COSMIC: COSV59617790; COSMIC: COSV59617790;