rs559835122

Variant names:

• chr20-48921865-C-T
• rs559835122
• NM_006420.3:c.-25C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_006420.3(ARFGEF2):​c.-25C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000363 in 1,514,012 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: ARFGEF2 NM_006420.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0290
• Publications: 0 publications found

Genes affected

ARFGEF2 (HGNC:15853): (ADP ribosylation factor guanine nucleotide exchange factor 2) ADP-ribosylation factors (ARFs) play an important role in intracellular vesicular trafficking. The protein encoded by this gene is involved in the activation of ARFs by accelerating replacement of bound GDP with GTP and is involved in Golgi transport. It contains a Sec7 domain, which may be responsible for its guanine-nucleotide exchange activity and also brefeldin A inhibition. [provided by RefSeq, Jul 2008]

ARFGEF2 Gene-Disease associations (from GenCC):

• periventricular heterotopia with microcephaly, autosomal recessive

  Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen
• periventricular nodular heterotopia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000294533 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 20-48921865-C-T is Benign according to our data. Variant chr20-48921865-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 516307.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00193 (292/151630) while in subpopulation AFR AF = 0.00678 (279/41162). AF 95% confidence interval is 0.00612. There are 1 homozygotes in GnomAd4. There are 141 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARFGEF2	NM_006420.3	c.-25C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 39	ENST00000371917.5	NP_006411.2
ARFGEF2	NM_006420.3	c.-25C>T		5_prime_UTR_variant	Exon 1 of 39	ENST00000371917.5	NP_006411.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARFGEF2	ENST00000371917.5	c.-25C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 39	1	NM_006420.3	ENSP00000360985.4
ARFGEF2	ENST00000371917.5	c.-25C>T		5_prime_UTR_variant	Exon 1 of 39	1	NM_006420.3	ENSP00000360985.4

Frequencies

GnomAD3 genomes AF: 0.00193 AC: 293 AN: 151520 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00682

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000265 AC: 33 AN: 124620 AF XY: 0.000283

Gnomad AFR exome AF: 0.00728

Gnomad AMR exome AF: 0.000142

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000290

GnomAD4 exome AF: 0.000189 AC: 258 AN: 1362382 Hom.: 0 Cov.: 31 AF XY: 0.000180 AC XY: 121 AN XY: 671754

African (AFR) AF: 0.00789 AC: 219 AN: 27752

American (AMR) AF: 0.000337 AC: 11 AN: 32614

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23860

East Asian (EAS) AF: 0.00 AC: 0 AN: 31534

South Asian (SAS) AF: 0.00 AC: 0 AN: 75982

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48078

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5472

European-Non Finnish (NFE) AF: 0.00000283 AC: 3 AN: 1061006

Other (OTH) AF: 0.000446 AC: 25 AN: 56084

GnomAD4 genome AF: 0.00193 AC: 292 AN: 151630 Hom.: 1 Cov.: 32 AF XY: 0.00190 AC XY: 141 AN XY: 74152

African (AFR) AF: 0.00678 AC: 279 AN: 41162

American (AMR) AF: 0.000655 AC: 10 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10550

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67890

Other (OTH) AF: 0.00143 AC: 3 AN: 2102

Alfa AF: 0.00187 Hom.: 0

Bravo AF: 0.00235

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Apr 30, 2018

GeneDx

Significance: Likely 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	-0.61
CADD	Benign	11
DANN	Benign	0.90
PhyloP100		-0.029
PromoterAI		-0.10	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs559835122; hg19: chr20-47538402;