11-6480015-C-A

Variant names:

• chr11-6480015-C-A
• rs1162697916
• NM_001376558.2:c.153G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001376562.2(ARFIP2):​c.17G>T​(p.Cys6Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C6Y) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ARFIP2 NM_001376562.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.317
• Publications: 0 publications found

Genes affected

ARFIP2 (HGNC:17160): (ADP ribosylation factor interacting protein 2) Enables several functions, including GTP-dependent protein binding activity; membrane curvature sensor activity; and phosphatidylinositol-4-phosphate binding activity. Involved in actin cytoskeleton organization. Located in cell cortex; ruffle; and trans-Golgi network membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09162897).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001376562.2. 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
	ARFIP2	NM_001376558.2	MANE Select	c.153G>T	p.Val51Val	synonymous	Exon 3 of 8	NP_001363487.1	P53365-1
	ARFIP2	NM_001376562.2		c.17G>T	p.Cys6Phe	missense	Exon 3 of 8	NP_001363491.1
	ARFIP2	NM_001242856.3		c.17G>T	p.Cys6Phe	missense	Exon 2 of 6	NP_001229785.1	P53365-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARFIP2	ENST00000396777.8	TSL:2 MANE Select	c.153G>T	p.Val51Val	synonymous	Exon 3 of 8	ENSP00000379998.3	P53365-1
	ARFIP2	ENST00000254584.6	TSL:1	c.153G>T	p.Val51Val	synonymous	Exon 3 of 8	ENSP00000254584.2	P53365-1
	ARFIP2	ENST00000445086.6	TSL:2	c.17G>T	p.Cys6Phe	missense	Exon 2 of 6	ENSP00000391427.2	P53365-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461882 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727246

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	7.3
DANN	Benign	0.84
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.092	T
MetaSVM	Benign	-0.66	T
PhyloP100		-0.32
PROVEAN	Benign	0.090	N
REVEL	Benign	0.24
Sift	Pathogenic	0.0	D
Vest4		0.21
MutPred		0.26		Loss of catalytic residue at L7 (P = 0.0232)
MVP		0.53
ClinPred		0.045	T
GERP RS		0.83
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1162697916; hg19: chr11-6501245;