22-19971288-C-T

Variant names:

• chr22-19971288-C-T
• rs35219372
• NM_001670.3:c.2829G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BS1 BS2

The NM_001670.3(ARVCF):​c.2829G>A​(p.Ala943Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0238 in 1,557,012 control chromosomes in the GnomAD database, including 536 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.017 (37 hom., cov: 34)
  • Exomes 𝑓: 0.025 (499 hom.)
• Consequence: ARVCF NM_001670.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.31
• Publications: 4 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP7: Synonymous conserved (PhyloP=-2.31 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0172 (2613/152328) while in subpopulation NFE AF = 0.0283 (1924/68030). AF 95% confidence interval is 0.0272. There are 37 homozygotes in GnomAd4. There are 1156 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 37 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001670.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARVCF	NM_001670.3	MANE Select	c.2829G>A	p.Ala943Ala	synonymous	Exon 19 of 20	NP_001661.1	O00192-1
	ARVCF	NM_001438684.1		c.2811G>A	p.Ala937Ala	synonymous	Exon 18 of 18	NP_001425613.1
	ARVCF	NM_001438685.1		c.2796G>A	p.Ala932Ala	synonymous	Exon 18 of 19	NP_001425614.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARVCF	ENST00000263207.8	TSL:1 MANE Select	c.2829G>A	p.Ala943Ala	synonymous	Exon 19 of 20	ENSP00000263207.3	O00192-1
	ARVCF	ENST00000406259.1	TSL:5	c.2811G>A	p.Ala937Ala	synonymous	Exon 16 of 16	ENSP00000385444.1	E9PDC3
	ARVCF	ENST00000852538.1		c.2796G>A	p.Ala932Ala	synonymous	Exon 18 of 19	ENSP00000522597.1

Frequencies

GnomAD3 genomes AF: 0.0172 AC: 2613 AN: 152210 Hom.: 37 Cov.: 34

Gnomad AFR AF: 0.00458

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0173

Gnomad ASJ AF: 0.0144

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00951

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0283

Gnomad OTH AF: 0.0234

GnomAD2 exomes AF: 0.0165 AC: 2695 AN: 163106 AF XY: 0.0170

Gnomad AFR exome AF: 0.00440

Gnomad AMR exome AF: 0.0119

Gnomad ASJ exome AF: 0.0172

Gnomad EAS exome AF: 0.0000814

Gnomad FIN exome AF: 0.00954

Gnomad NFE exome AF: 0.0301

Gnomad OTH exome AF: 0.0164

GnomAD4 exome AF: 0.0245 AC: 34418 AN: 1404684 Hom.: 499 Cov.: 35 AF XY: 0.0238 AC XY: 16489 AN XY: 693340

African (AFR) AF: 0.00398 AC: 128 AN: 32162

American (AMR) AF: 0.0121 AC: 445 AN: 36660

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 387 AN: 25214

East Asian (EAS) AF: 0.00 AC: 0 AN: 36528

South Asian (SAS) AF: 0.00209 AC: 167 AN: 79842

European-Finnish (FIN) AF: 0.0100 AC: 488 AN: 48672

Middle Eastern (MID) AF: 0.0147 AC: 84 AN: 5706

European-Non Finnish (NFE) AF: 0.0290 AC: 31420 AN: 1081736

Other (OTH) AF: 0.0223 AC: 1299 AN: 58164

GnomAD4 genome AF: 0.0172 AC: 2613 AN: 152328 Hom.: 37 Cov.: 34 AF XY: 0.0155 AC XY: 1156 AN XY: 74488

African (AFR) AF: 0.00457 AC: 190 AN: 41572

American (AMR) AF: 0.0173 AC: 265 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0144 AC: 50 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4828

European-Finnish (FIN) AF: 0.00951 AC: 101 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0283 AC: 1924 AN: 68030

Other (OTH) AF: 0.0232 AC: 49 AN: 2112

Alfa AF: 0.0209 Hom.: 51

Bravo AF: 0.0180

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	1.0
DANN	Benign	0.95
PhyloP100		-2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	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: rs35219372; hg19: chr22-19958811;