NM_203437.4:c.2271+4A>C

Variant names:

• chr2-64569683-A-C
• rs2287531
• NM_203437.4:c.2271+4A>C

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 1P and 8B. PP3 BA1

The NM_203437.4(AFTPH):​c.2271+4A>C variant causes a splice 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. 2/3 splice prediction tools predicting alterations to normal splicing. 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_region, intron
• Scores: Splicing: ADA: 0.9872
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.78
• Publications: 6 publications found

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

Our verdict: Benign. The variant received -7 ACMG points.

• PP3: Splicing predictors support a deleterious 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_203437.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFTPH	NM_203437.4	MANE Select	c.2271+4A>C		splice_region intron	N/A	NP_982261.2
	AFTPH	NM_001375969.1		c.2271+4A>C		splice_region intron	N/A	NP_001362898.1
	AFTPH	NM_001375970.1		c.2271+4A>C		splice_region intron	N/A	NP_001362899.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFTPH	ENST00000409933.6	TSL:1 MANE Select	c.2271+4A>C		splice_region intron	N/A	ENSP00000387071.1
	AFTPH	ENST00000238856.8	TSL:1	c.2271+4A>C		splice_region intron	N/A	ENSP00000238856.4
	AFTPH	ENST00000498706.5	TSL:1	n.2389+4A>C		splice_region intron	N/A

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

GnomAD2 exomes AF: 0.0172 AC: 4312 AN: 250974 AF XY: 0.0154

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 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

African (AFR) AF: 0.0659 AC: 2204 AN: 33434

American (AMR) AF: 0.00436 AC: 195 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00387 AC: 101 AN: 26110

East Asian (EAS) AF: 0.136 AC: 5394 AN: 39570

South Asian (SAS) AF: 0.00670 AC: 578 AN: 86234

European-Finnish (FIN) AF: 0.00174 AC: 93 AN: 53354

Middle Eastern (MID) AF: 0.0154 AC: 89 AN: 5764

European-Non Finnish (NFE) AF: 0.000890 AC: 989 AN: 1111490

Other (OTH) AF: 0.0142 AC: 858 AN: 60358

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

African (AFR) AF: 0.0640 AC: 2659 AN: 41566

American (AMR) AF: 0.00810 AC: 124 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00576 AC: 20 AN: 3470

East Asian (EAS) AF: 0.136 AC: 707 AN: 5184

South Asian (SAS) AF: 0.00869 AC: 42 AN: 4834

European-Finnish (FIN) AF: 0.00160 AC: 17 AN: 10626

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00112 AC: 76 AN: 68026

Other (OTH) AF: 0.0170 AC: 36 AN: 2112

Alfa AF: 0.00869 Hom.: 55

Bravo AF: 0.0271

EpiCase AF: 0.00175

EpiControl AF: 0.00107

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Uncertain	0.98
PhyloP100		8.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Mutation Taster		=86/14	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2287531; hg19: chr2-64796817; COSMIC: COSV53218440;