rs5993891

Variant names:

• chr22-19972223-C-T
• rs5993891
• NM_001670.3:c.2695+135G>A

Variant summary

Our verdict is Benign. The variant received -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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
ARVCF	NM_001670.3	c.2695+135G>A		intron_variant	Intron 17 of 19	ENST00000263207.8	NP_001661.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARVCF	ENST00000263207.8	c.2695+135G>A		intron_variant	Intron 17 of 19	1	NM_001670.3	ENSP00000263207.3

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 AC: 9218 AN: 25310

Gnomad4 AMR exome AF: 0.0827 AC: 2846 AN: 34400

Gnomad4 ASJ exome AF: 0.0941 AC: 1939 AN: 20596

Gnomad4 EAS exome AF: 0.0298 AC: 1047 AN: 35086

Gnomad4 SAS exome AF: 0.111 AC: 7600 AN: 68200

Gnomad4 FIN exome AF: 0.0285 AC: 1366 AN: 47870

Gnomad4 NFE exome AF: 0.0467 AC: 37133 AN: 794878

Gnomad4 Remaining exome AF: 0.0812 AC: 3845 AN: 47372

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 AC: 0.359514 AN: 0.359514

Gnomad4 AMR AF: 0.0971 AC: 0.0971496 AN: 0.0971496

Gnomad4 ASJ AF: 0.0888 AC: 0.088812 AN: 0.088812

Gnomad4 EAS AF: 0.0315 AC: 0.0314915 AN: 0.0314915

Gnomad4 SAS AF: 0.104 AC: 0.103563 AN: 0.103563

Gnomad4 FIN AF: 0.0236 AC: 0.0236213 AN: 0.0236213

Gnomad4 NFE AF: 0.0479 AC: 0.0478753 AN: 0.0478753

Gnomad4 OTH AF: 0.131 AC: 0.130806 AN: 0.130806

Alfa AF: 0.0705 Hom.: 1093

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 10, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.44
DANN	Benign	0.61
Mutation Taster		=100/0	polymorphism (auto)

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;