22-19971269-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.2848G>A(p.Val950Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000308 in 1,556,548 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: ARVCF NM_001670.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.90

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=0.10529569).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARVCF	NM_001670.3	c.2848G>A	p.Val950Ile	missense_variant	19/20	ENST00000263207.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARVCF	ENST00000263207.8	c.2848G>A	p.Val950Ile	missense_variant	19/20	1	NM_001670.3	P4

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152232 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000674 AC: 11 AN: 163196 Hom.: 0 AF XY: 0.0000579 AC XY: 5 AN XY: 86282

Gnomad AFR exome AF: 0.000210

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000814

Gnomad SAS exome AF: 0.000258

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000312

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000299 AC: 42 AN: 1404198 Hom.: 0 Cov.: 35 AF XY: 0.0000317 AC XY: 22 AN XY: 693014

Gnomad4 AFR exome AF: 0.000125

Gnomad4 AMR exome AF: 0.0000273

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000238

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000129

Gnomad4 OTH exome AF: 0.0000688

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152350 Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2 AN XY: 74486

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000659 Hom.: 0

Bravo AF: 0.0000416

ESP6500AA AF: 0.000232 AC: 1

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.0000445 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 20, 2023

The c.2848G>A (p.V950I) 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 2848, causing the valine (V) at amino acid position 950 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.0077	T;.;T;.
Eigen	Benign	-0.0098
Eigen_PC	Benign	0.080
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.87	D;D;D;D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.11	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.2	L;.;.;.
MutationTaster	Benign	0.99	N;N;N;N;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.20	N;N;N;N
REVEL	Benign	0.11
Sift	Benign	0.068	T;T;T;T
Sift4G	Benign	0.42	T;T;T;T
Polyphen		0.81	P;.;.;.
Vest4		0.33
MVP		0.67
MPC		0.12
ClinPred		0.062	T
GERP RS		3.0
Varity_R		0.070
gMVP		0.098

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: rs142907270; hg19: chr22-19958792;