22-19971950-C-G

Variant names:

• chr22-19971950-C-G
• rs165815
• NM_001670.3:c.2717G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001670.3(ARVCF):​c.2717G>C​(p.Arg906Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 16/22 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 Benign.

• Frequency: Genomes: not found (cov: 35)
• Consequence: ARVCF NM_001670.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.89
• Publications: 67 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001670.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARVCF	NM_001670.3	MANE Select	c.2717G>C	p.Arg906Pro	missense	Exon 18 of 20	NP_001661.1	O00192-1
	ARVCF	NM_001438684.1		c.2699G>C	p.Arg900Pro	missense	Exon 17 of 18	NP_001425613.1
	ARVCF	NM_001438685.1		c.2684G>C	p.Arg895Pro	missense	Exon 17 of 19	NP_001425614.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARVCF	ENST00000263207.8	TSL:1 MANE Select	c.2717G>C	p.Arg906Pro	missense	Exon 18 of 20	ENSP00000263207.3	O00192-1
	ARVCF	ENST00000406259.1	TSL:5	c.2699G>C	p.Arg900Pro	missense	Exon 15 of 16	ENSP00000385444.1	E9PDC3
	ARVCF	ENST00000852538.1		c.2684G>C	p.Arg895Pro	missense	Exon 17 of 19	ENSP00000522597.1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Cov.: 55

GnomAD4 genome Cov.: 35

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	17
DANN	Benign	0.92
DEOGEN2	Benign	0.023	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.063	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.9
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.22
Sift	Benign	0.11	T
Sift4G	Benign	0.34	T
Polyphen		0.0010	B
Vest4		0.46
MutPred		0.14		Loss of MoRF binding (P = 0.0017)
MVP		0.68
MPC		0.37
ClinPred		0.42	T
GERP RS		1.9
Varity_R		0.11
gMVP		0.32
Mutation Taster		=79/21	polymorphism

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

Other links and lift over

dbSNP: rs165815; hg19: chr22-19959473;