rs2287531

Positions:

• chr2-64569683-A-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP3 BA1

The NM_203437.4(AFTPH):​c.2271+4A>C variant causes a splice donor region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00879 in 1,613,346 control chromosomes in the GnomAD database, including 621 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 0.024 (145 hom., cov: 33)
  • Exomes 𝑓: 0.0072 (476 hom.)
• Consequence: AFTPH NM_203437.4 splice_donor_region, intron
• Scores: Splicing: ADA: 0.9872
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.78

Genes affected

AFTPH (HGNC:25951): (aftiphilin) Enables clathrin binding activity. Predicted to be involved in intracellular transport. Located in Golgi apparatus; cytosol; and nucleoplasm. Part of AP-1 adaptor complex. [provided by Alliance of Genome Resources, Apr 2022]

LOC105374773 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.128 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AFTPH	NM_203437.4	c.2271+4A>C		splice_donor_region_variant, intron_variant		ENST00000409933.6	NP_982261.2
LOC105374773	XR_007086343.1	n.614-7440T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AFTPH	ENST00000409933.6	c.2271+4A>C		splice_donor_region_variant, intron_variant		1	NM_203437.4	ENSP00000387071	A1

Frequencies

GnomAD3 genomes AF: 0.0242 AC: 3682 AN: 152206 Hom.: 145 Cov.: 33

Gnomad AFR AF: 0.0641

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00812

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.136

Gnomad SAS AF: 0.00889

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00112

Gnomad OTH AF: 0.0172

GnomAD3 exomes AF: 0.0172 AC: 4312 AN: 250974 Hom.: 237 AF XY: 0.0154 AC XY: 2094 AN XY: 135654

Gnomad AFR exome AF: 0.0668

Gnomad AMR exome AF: 0.00354

Gnomad ASJ exome AF: 0.00457

Gnomad EAS exome AF: 0.144

Gnomad SAS exome AF: 0.00615

Gnomad FIN exome AF: 0.00167

Gnomad NFE exome AF: 0.00127

Gnomad OTH exome AF: 0.00768

GnomAD4 exome AF: 0.00719 AC: 10501 AN: 1461022 Hom.: 476 Cov.: 30 AF XY: 0.00701 AC XY: 5097 AN XY: 726846

Gnomad4 AFR exome AF: 0.0659

Gnomad4 AMR exome AF: 0.00436

Gnomad4 ASJ exome AF: 0.00387

Gnomad4 EAS exome AF: 0.136

Gnomad4 SAS exome AF: 0.00670

Gnomad4 FIN exome AF: 0.00174

Gnomad4 NFE exome AF: 0.000890

Gnomad4 OTH exome AF: 0.0142

GnomAD4 genome AF: 0.0242 AC: 3685 AN: 152324 Hom.: 145 Cov.: 33 AF XY: 0.0245 AC XY: 1827 AN XY: 74488

Gnomad4 AFR AF: 0.0640

Gnomad4 AMR AF: 0.00810

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.136

Gnomad4 SAS AF: 0.00869

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.00112

Gnomad4 OTH AF: 0.0170

Alfa AF: 0.00675 Hom.: 38

Bravo AF: 0.0271

EpiCase AF: 0.00175

EpiControl AF: 0.00107

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Uncertain	0.98
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.81
SpliceAI score (max)		0.060		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: rs2287531; hg19: chr2-64796817; COSMIC: COSV53218440;