rs16982871

Positions:

• chr22-19978040-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001670.3(ARVCF):​c.1616G>A​(p.Arg539Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0096 in 1,611,380 control chromosomes in the GnomAD database, including 88 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0059 (6 hom., cov: 33)
  • Exomes 𝑓: 0.010 (82 hom.)
• Consequence: ARVCF NM_001670.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.54

Genes affected

ARVCF (HGNC:728): (ARVCF delta catenin family member) Armadillo Repeat gene deleted in Velo-Cardio-Facial syndrome (ARVCF) is a member of the catenin family. This family plays an important role in the formation of adherens junction complexes, which are thought to facilitate communication between the inside and outside environments of a cell. The ARVCF gene was isolated in the search for the genetic defect responsible for the autosomal dominant Velo-Cardio-Facial syndrome (VCFS), a relatively common human disorder with phenotypic features including cleft palate, conotruncal heart defects and facial dysmorphology. The ARVCF gene encodes a protein containing two motifs, a coiled coil domain in the N-terminus and a 10 armadillo repeat sequence in the midregion. Since these sequences can facilitate protein-protein interactions ARVCF is thought to function in a protein complex. In addition, ARVCF contains a predicted nuclear-targeting sequence suggesting that it may have a function as a nuclear protein. [provided by RefSeq, Jun 2010]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011663407).
• BP6: Variant 22-19978040-C-T is Benign according to our data. Variant chr22-19978040-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 445517.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARVCF	NM_001670.3	c.1616G>A	p.Arg539Gln	missense_variant	8/20	ENST00000263207.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARVCF	ENST00000263207.8	c.1616G>A	p.Arg539Gln	missense_variant	8/20	1	NM_001670.3	P4

Frequencies

GnomAD3 genomes AF: 0.00593 AC: 903 AN: 152210 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00186

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00558

Gnomad FIN AF: 0.00292

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0106

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00630 AC: 1563 AN: 248266 Hom.: 13 AF XY: 0.00657 AC XY: 885 AN XY: 134750

Gnomad AFR exome AF: 0.00143

Gnomad AMR exome AF: 0.00166

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00525

Gnomad FIN exome AF: 0.00314

Gnomad NFE exome AF: 0.0109

Gnomad OTH exome AF: 0.00579

GnomAD4 exome AF: 0.00998 AC: 14564 AN: 1459052 Hom.: 82 Cov.: 31 AF XY: 0.00981 AC XY: 7117 AN XY: 725712

Gnomad4 AFR exome AF: 0.00149

Gnomad4 AMR exome AF: 0.00153

Gnomad4 ASJ exome AF: 0.000192

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00620

Gnomad4 FIN exome AF: 0.00395

Gnomad4 NFE exome AF: 0.0119

Gnomad4 OTH exome AF: 0.00783

GnomAD4 genome AF: 0.00592 AC: 902 AN: 152328 Hom.: 6 Cov.: 33 AF XY: 0.00542 AC XY: 404 AN XY: 74488

Gnomad4 AFR AF: 0.00185

Gnomad4 AMR AF: 0.00248

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00538

Gnomad4 FIN AF: 0.00292

Gnomad4 NFE AF: 0.0106

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00937 Hom.: 10

Bravo AF: 0.00561

TwinsUK AF: 0.0124 AC: 46

ALSPAC AF: 0.0122 AC: 47

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00919 AC: 79

ExAC AF: 0.00728 AC: 883

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0103

EpiControl AF: 0.00937

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	ARVCF: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jul 18, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.017	T;.;T;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.52	D
LIST_S2	Uncertain	0.94	D;D;D;D
MetaRNN	Benign	0.012	T;T;T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	1.4	L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.5	N;N;N;N
REVEL	Benign	0.28
Sift	Benign	0.19	T;T;T;T
Sift4G	Benign	0.30	T;T;T;T
Polyphen		0.99	D;.;.;.
Vest4		0.52
MVP		0.80
MPC		0.48
ClinPred		0.021	T
GERP RS		4.0
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.8
Varity_R		0.31
gMVP		0.60

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: rs16982871; hg19: chr22-19965563; COSMIC: COSV99070614; COSMIC: COSV99070614;