22-19971245-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001670.3(ARVCF):c.2872G>A(p.Val958Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000113 in 1,555,286 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: ARVCF NM_001670.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.38

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13378367).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARVCF	NM_001670.3	c.2872G>A	p.Val958Ile	missense_variant	19/20	ENST00000263207.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARVCF	ENST00000263207.8	c.2872G>A	p.Val958Ile	missense_variant	19/20	1	NM_001670.3	P4

Frequencies

GnomAD3 genomes AF: 0.0000985 AC: 15 AN: 152252 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000162

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000234 AC: 38 AN: 162058 Hom.: 0 AF XY: 0.000211 AC XY: 18 AN XY: 85432

Gnomad AFR exome AF: 0.000212

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00117

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000142

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000115 AC: 161 AN: 1402916 Hom.: 0 Cov.: 35 AF XY: 0.000120 AC XY: 83 AN XY: 692268

Gnomad4 AFR exome AF: 0.0000626

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000918

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000694

Gnomad4 OTH exome AF: 0.0000860

GnomAD4 genome AF: 0.0000984 AC: 15 AN: 152370 Hom.: 0 Cov.: 34 AF XY: 0.0000939 AC XY: 7 AN XY: 74518

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000954 Hom.: 0

Bravo AF: 0.0000907

ESP6500AA AF: 0.000231 AC: 1

ESP6500EA AF: 0.000588 AC: 5

ExAC AF: 0.000145 AC: 16

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 03, 2022

The c.2872G>A (p.V958I) alteration is located in exon 19 (coding exon 17) of the ARVCF gene. This alteration results from a G to A substitution at nucleotide position 2872, causing the valine (V) at amino acid position 958 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.32
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.010	T;.;T;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.13	T;T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	1.6	L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.18	N;N;N;N
REVEL	Benign	0.16
Sift	Uncertain	0.011	D;D;D;D
Sift4G	Benign	0.13	T;T;T;T
Polyphen		0.98	D;.;.;.
Vest4		0.50
MVP		0.77
MPC		0.51
ClinPred		0.13	T
GERP RS		4.1
Varity_R		0.14
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs72554700; hg19: chr22-19958768;