rs5993891

Positions:

• chr22-19972223-C-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.2695+135G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0704 in 1,230,822 control chromosomes in the GnomAD database, including 6,606 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (2925 hom., cov: 33)
  • Exomes 𝑓: 0.061 (3681 hom.)
• Consequence: ARVCF NM_001670.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.17

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=-0.85).
• BP6: Variant 22-19972223-C-T is Benign according to our data. Variant chr22-19972223-C-T is described in ClinVar as [Benign]. Clinvar id is 1233397.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.355 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARVCF	NM_001670.3	c.2695+135G>A		intron_variant		ENST00000263207.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARVCF	ENST00000263207.8	c.2695+135G>A		intron_variant		1	NM_001670.3	P4

Frequencies

GnomAD3 genomes AF: 0.139 AC: 21193 AN: 152058 Hom.: 2908 Cov.: 33

Gnomad AFR AF: 0.359

Gnomad AMI AF: 0.0877

Gnomad AMR AF: 0.0973

Gnomad ASJ AF: 0.0888

Gnomad EAS AF: 0.0320

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.0236

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0479

Gnomad OTH AF: 0.132

GnomAD4 exome AF: 0.0607 AC: 65453 AN: 1078646 Hom.: 3681 AF XY: 0.0616 AC XY: 33369 AN XY: 541514

Gnomad4 AFR exome AF: 0.364

Gnomad4 AMR exome AF: 0.0827

Gnomad4 ASJ exome AF: 0.0941

Gnomad4 EAS exome AF: 0.0298

Gnomad4 SAS exome AF: 0.111

Gnomad4 FIN exome AF: 0.0285

Gnomad4 NFE exome AF: 0.0467

Gnomad4 OTH exome AF: 0.0812

GnomAD4 genome AF: 0.140 AC: 21246 AN: 152176 Hom.: 2925 Cov.: 33 AF XY: 0.136 AC XY: 10113 AN XY: 74394

Gnomad4 AFR AF: 0.360

Gnomad4 AMR AF: 0.0971

Gnomad4 ASJ AF: 0.0888

Gnomad4 EAS AF: 0.0315

Gnomad4 SAS AF: 0.104

Gnomad4 FIN AF: 0.0236

Gnomad4 NFE AF: 0.0479

Gnomad4 OTH AF: 0.131

Alfa AF: 0.0673 Hom.: 810

Bravo AF: 0.154

Asia WGS AF: 0.0890 AC: 313 AN: 3478

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.44
DANN	Benign	0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs5993891; hg19: chr22-19959746;