rs165849

Positions:

• chr22-19971146-G-A
• chr22-19971146-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001670.3(ARVCF):​c.*12+70C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.654 in 1,540,188 control chromosomes in the GnomAD database, including 336,887 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (24885 hom., cov: 33)
  • Exomes 𝑓: 0.66 (312002 hom.)
• Consequence: ARVCF NM_001670.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.625

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 22-19971146-G-A is Benign according to our data. Variant chr22-19971146-G-A is described in ClinVar as [Benign]. Clinvar id is 1280000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.689 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARVCF	NM_001670.3	c.*12+70C>T		intron_variant		ENST00000263207.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARVCF	ENST00000263207.8	c.*12+70C>T		intron_variant		1	NM_001670.3	P4
ARVCF	ENST00000495096.5	n.1704-403C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.555 AC: 81732 AN: 147194 Hom.: 24892 Cov.: 33

Gnomad AFR AF: 0.269

Gnomad AMI AF: 0.795

Gnomad AMR AF: 0.536

Gnomad ASJ AF: 0.608

Gnomad EAS AF: 0.499

Gnomad SAS AF: 0.567

Gnomad FIN AF: 0.666

Gnomad MID AF: 0.652

Gnomad NFE AF: 0.694

Gnomad OTH AF: 0.574

GnomAD4 exome AF: 0.664 AC: 924890 AN: 1392884 Hom.: 312002 AF XY: 0.662 AC XY: 454651 AN XY: 687226

Gnomad4 AFR exome AF: 0.255

Gnomad4 AMR exome AF: 0.509

Gnomad4 ASJ exome AF: 0.595

Gnomad4 EAS exome AF: 0.521

Gnomad4 SAS exome AF: 0.550

Gnomad4 FIN exome AF: 0.670

Gnomad4 NFE exome AF: 0.696

Gnomad4 OTH exome AF: 0.627

GnomAD4 genome AF: 0.555 AC: 81723 AN: 147304 Hom.: 24885 Cov.: 33 AF XY: 0.553 AC XY: 39873 AN XY: 72070

Gnomad4 AFR AF: 0.268

Gnomad4 AMR AF: 0.535

Gnomad4 ASJ AF: 0.608

Gnomad4 EAS AF: 0.499

Gnomad4 SAS AF: 0.566

Gnomad4 FIN AF: 0.666

Gnomad4 NFE AF: 0.694

Gnomad4 OTH AF: 0.573

Alfa AF: 0.591 Hom.: 4155

Bravo AF: 0.514

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 10, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.6
DANN	Benign	0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs165849; hg19: chr22-19958669; COSMIC: COSV52889019; COSMIC: COSV52889019;