chr22-19971899-T-G

Variant names:

• chr22-19971899-T-G
• rs377217563
• NM_001670.3:c.2768A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001670.3(ARVCF):​c.2768A>C​(p.Lys923Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,028 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ARVCF NM_001670.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.52
• Publications: 1 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16952857).

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.2768A>C	p.Lys923Thr	missense	Exon 18 of 20	NP_001661.1	O00192-1
	ARVCF	NM_001438684.1		c.2750A>C	p.Lys917Thr	missense	Exon 17 of 18	NP_001425613.1
	ARVCF	NM_001438685.1		c.2735A>C	p.Lys912Thr	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.2768A>C	p.Lys923Thr	missense	Exon 18 of 20	ENSP00000263207.3	O00192-1
	ARVCF	ENST00000406259.1	TSL:5	c.2750A>C	p.Lys917Thr	missense	Exon 15 of 16	ENSP00000385444.1	E9PDC3
	ARVCF	ENST00000852538.1		c.2735A>C	p.Lys912Thr	missense	Exon 17 of 19	ENSP00000522597.1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 250922 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461028 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 726856

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52794

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111858

Other (OTH) AF: 0.0000166 AC: 1 AN: 60366

GnomAD4 genome Cov.: 35

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0077	T
Eigen	Benign	-0.076
Eigen_PC	Benign	-0.016
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.7	L
PhyloP100		2.5
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.57	N
REVEL	Benign	0.097
Sift	Benign	0.14	T
Sift4G	Benign	0.31	T
Polyphen		0.015	B
Vest4		0.25
MutPred		0.18		Loss of ubiquitination at K923 (P = 1e-04)
MVP		0.76
MPC		0.14
ClinPred		0.23	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.23
Mutation Taster		=84/16	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: rs377217563; hg19: chr22-19959422;