chr22-19972223-C-T

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
• Publications: 21 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=-0.85).
• 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

African (AFR) AF: 0.364 AC: 9218 AN: 25310

American (AMR) AF: 0.0827 AC: 2846 AN: 34400

Ashkenazi Jewish (ASJ) AF: 0.0941 AC: 1939 AN: 20596

East Asian (EAS) AF: 0.0298 AC: 1047 AN: 35086

South Asian (SAS) AF: 0.111 AC: 7600 AN: 68200

European-Finnish (FIN) AF: 0.0285 AC: 1366 AN: 47870

Middle Eastern (MID) AF: 0.0930 AC: 459 AN: 4934

European-Non Finnish (NFE) AF: 0.0467 AC: 37133 AN: 794878

Other (OTH) 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

African (AFR) AF: 0.360 AC: 14904 AN: 41456

American (AMR) AF: 0.0971 AC: 1486 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0888 AC: 308 AN: 3468

East Asian (EAS) AF: 0.0315 AC: 163 AN: 5176

South Asian (SAS) AF: 0.104 AC: 500 AN: 4828

European-Finnish (FIN) AF: 0.0236 AC: 251 AN: 10626

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0479 AC: 3256 AN: 68010

Other (OTH) AF: 0.131 AC: 276 AN: 2110

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
PhyloP100		-2.2
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

Other links and lift over

dbSNP: rs5993891; hg19: chr22-19959746;