4-152888271-T-A

Variant names:

• chr4-152888271-T-A
• rs1165541263
• NM_001025595.3:c.930T>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001025595.3(ARFIP1):​c.930T>A​(p.Asp310Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,455,912 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ARFIP1 NM_001025595.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.95

Genes affected

ARFIP1 (HGNC:21496): (ADP ribosylation factor interacting protein 1) Enables phosphatidylinositol-4-phosphate binding activity. Involved in negative regulation of retrograde transport, endosome to Golgi. Acts upstream of or within intracellular protein transport and regulation of protein secretion. Located in Golgi membrane; cytosol; and trans-Golgi network membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.955

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARFIP1	NM_001025595.3	c.930T>A	p.Asp310Glu	missense_variant	Exon 8 of 9	ENST00000353617.7	NP_001020766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARFIP1	ENST00000353617.7	c.930T>A	p.Asp310Glu	missense_variant	Exon 8 of 9	5	NM_001025595.3	ENSP00000296557.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000818 AC: 2 AN: 244496 Hom.: 0 AF XY: 0.0000151 AC XY: 2 AN XY: 132244

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000110

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1455912 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2 AN XY: 724240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000506

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.930T>A (p.D310E) alteration is located in exon 8 (coding exon 7) of the ARFIP1 gene. This alteration results from a T to A substitution at nucleotide position 930, causing the aspartic acid (D) at amino acid position 310 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T;T;.;.;.
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	D;.;D;.;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Uncertain	2.4	M;M;.;.;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.6	D;D;D;D;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.020	D;D;D;D;D
Sift4G	Uncertain	0.060	T;T;T;D;D
Polyphen		1.0	D;D;.;.;.
Vest4		0.86
MutPred		0.85		Gain of methylation at K314 (P = 0.1205);Gain of methylation at K314 (P = 0.1205);.;.;.;
MVP		0.96
MPC		0.53
ClinPred		0.93	D
GERP RS		3.4
Varity_R		0.44
gMVP		0.58

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

Publications

LitVar

Other links and lift over

dbSNP: rs1165541263; hg19: chr4-153809423;