rs165815

Positions:

• chr22-19971950-C-A
• chr22-19971950-C-G
• chr22-19971950-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001670.3(ARVCF):​c.2717G>T​(p.Arg906Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R906Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 35)
• Consequence: ARVCF NM_001670.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.89

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3478203).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARVCF	NM_001670.3	c.2717G>T	p.Arg906Leu	missense_variant	18/20	ENST00000263207.8	NP_001661.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARVCF	ENST00000263207.8	c.2717G>T	p.Arg906Leu	missense_variant	18/20	1	NM_001670.3	ENSP00000263207	P4

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Cov.: 55

GnomAD4 genome Cov.: 35

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.018	T;.;T;.
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.75	T;D;D;T
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.35	T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.4	L;.;.;.
MutationTaster	Benign	0.15	P;P;P;P;P
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.88	N;N;N;N
REVEL	Benign	0.099
Sift	Uncertain	0.017	D;D;D;D
Sift4G	Benign	0.29	T;T;T;T
Polyphen		0.11	B;.;.;.
Vest4		0.27
MutPred		0.13		Loss of MoRF binding (P = 0.0131);.;.;.;
MVP		0.69
MPC		0.17
ClinPred		0.24	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.060
gMVP		0.24

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: rs165815; hg19: chr22-19959473;