22-19971146-G-A

Variant names:

• chr22-19971146-G-A
• rs165849
• NM_001670.3:c.*12+70C>T

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.*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
• Publications: 23 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: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
ARVCF	NM_001670.3	c.*12+70C>T		intron_variant	Intron 19 of 19	ENST00000263207.8	NP_001661.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARVCF	ENST00000263207.8	c.*12+70C>T		intron_variant	Intron 19 of 19	1	NM_001670.3	ENSP00000263207.3

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

African (AFR) AF: 0.255 AC: 7190 AN: 28168

American (AMR) AF: 0.509 AC: 18051 AN: 35452

Ashkenazi Jewish (ASJ) AF: 0.595 AC: 14937 AN: 25110

East Asian (EAS) AF: 0.521 AC: 18618 AN: 35716

South Asian (SAS) AF: 0.550 AC: 43513 AN: 79116

European-Finnish (FIN) AF: 0.670 AC: 32236 AN: 48102

Middle Eastern (MID) AF: 0.628 AC: 3557 AN: 5662

European-Non Finnish (NFE) AF: 0.696 AC: 750669 AN: 1077908

Other (OTH) AF: 0.627 AC: 36119 AN: 57650

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

African (AFR) AF: 0.268 AC: 9881 AN: 36860

American (AMR) AF: 0.535 AC: 8111 AN: 15170

Ashkenazi Jewish (ASJ) AF: 0.608 AC: 2106 AN: 3462

East Asian (EAS) AF: 0.499 AC: 2579 AN: 5168

South Asian (SAS) AF: 0.566 AC: 2730 AN: 4820

European-Finnish (FIN) AF: 0.666 AC: 7061 AN: 10600

Middle Eastern (MID) AF: 0.653 AC: 192 AN: 294

European-Non Finnish (NFE) AF: 0.694 AC: 47150 AN: 67944

Other (OTH) AF: 0.573 AC: 1188 AN: 2074

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

May 10, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.6
DANN	Benign	0.87
PhyloP100		0.63
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs165849; hg19: chr22-19958669; COSMIC: COSV52889019; COSMIC: COSV52889019;