2-64552471-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_203437.4(AFTPH):ā€‹c.997A>Gā€‹(p.Lys333Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000021 ( 0 hom. )

Consequence

AFTPH
NM_203437.4 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0700
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.023710757).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
AFTPHNM_203437.4 linkuse as main transcriptc.997A>G p.Lys333Glu missense_variant 2/10 ENST00000409933.6 NP_982261.2
LOC105374773XR_007086343.1 linkuse as main transcriptn.5406-1207T>C intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
AFTPHENST00000409933.6 linkuse as main transcriptc.997A>G p.Lys333Glu missense_variant 2/101 NM_203437.4 ENSP00000387071 A1Q6ULP2-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461738
Hom.:
0
Cov.:
32
AF XY:
0.00000275
AC XY:
2
AN XY:
727158
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 18, 2024The c.997A>G (p.K333E) alteration is located in exon 2 (coding exon 1) of the AFTPH gene. This alteration results from a A to G substitution at nucleotide position 997, causing the lysine (K) at amino acid position 333 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
Benign
0.060
BayesDel_addAF
Benign
-0.38
T
BayesDel_noAF
Benign
-0.79
CADD
Benign
2.8
DANN
Benign
0.54
DEOGEN2
Benign
0.0012
T;.;T
Eigen
Benign
-1.5
Eigen_PC
Benign
-1.5
FATHMM_MKL
Benign
0.050
N
LIST_S2
Benign
0.62
T;T;.
M_CAP
Benign
0.0037
T
MetaRNN
Benign
0.024
T;T;T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
1.0
L;L;L
MutationTaster
Benign
1.0
N;N;N;N
PrimateAI
Benign
0.28
T
PROVEAN
Benign
-0.26
N;N;N
REVEL
Benign
0.025
Sift
Benign
0.99
T;T;T
Sift4G
Benign
1.0
T;T;T
Polyphen
0.0
B;.;B
Vest4
0.063
MutPred
0.34
Loss of ubiquitination at K333 (P = 0.0087);Loss of ubiquitination at K333 (P = 0.0087);Loss of ubiquitination at K333 (P = 0.0087);
MVP
0.12
MPC
0.13
ClinPred
0.035
T
GERP RS
-4.5
Varity_R
0.061
gMVP
0.089

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-64779605; API