chr15-67204142-A-G
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2
The NM_024666.5(AAGAB):c.722T>C(p.Met241Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000414 in 1,594,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000045 ( 0 hom. )
Consequence
AAGAB
NM_024666.5 missense
NM_024666.5 missense
Scores
5
14
Clinical Significance
Conservation
PhyloP100: 4.60
Genes affected
AAGAB (HGNC:25662): (alpha and gamma adaptin binding protein) The protein encoded by this gene interacts with the gamma-adaptin and alpha-adaptin subunits of complexes involved in clathrin-coated vesicle trafficking. Mutations in this gene are associated with type I punctate palmoplantar keratoderma. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2012]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -7 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.13803971).
BS1
?
Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000451 (65/1441982) while in subpopulation EAS AF= 0.00149 (59/39586). AF 95% confidence interval is 0.00119. There are 0 homozygotes in gnomad4_exome. There are 31 alleles in male gnomad4_exome subpopulation. Median coverage is 26. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
?
High AC in GnomAdExome at 8 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AAGAB | NM_024666.5 | c.722T>C | p.Met241Thr | missense_variant | 8/10 | ENST00000261880.10 | |
AAGAB | NM_001271885.2 | c.395T>C | p.Met132Thr | missense_variant | 8/10 | ||
AAGAB | NM_001271886.2 | c.395T>C | p.Met132Thr | missense_variant | 8/10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AAGAB | ENST00000261880.10 | c.722T>C | p.Met241Thr | missense_variant | 8/10 | 1 | NM_024666.5 | P1 | |
AAGAB | ENST00000542650.5 | c.395T>C | p.Met132Thr | missense_variant | 8/10 | 2 | |||
AAGAB | ENST00000561452.5 | c.395T>C | p.Met132Thr | missense_variant | 8/10 | 5 | |||
AAGAB | ENST00000538028.1 | n.403T>C | non_coding_transcript_exon_variant | 5/7 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152218Hom.: 0 Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.0000323 AC: 8AN: 247632Hom.: 0 AF XY: 0.0000521 AC XY: 7AN XY: 134352
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GnomAD4 exome AF: 0.0000451 AC: 65AN: 1441982Hom.: 0 Cov.: 26 AF XY: 0.0000431 AC XY: 31AN XY: 718512
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3478
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 submitter | clinical testing | Ambry Genetics | May 18, 2023 | The c.722T>C (p.M241T) alteration is located in exon 8 (coding exon 8) of the AAGAB gene. This alteration results from a T to C substitution at nucleotide position 722, causing the methionine (M) at amino acid position 241 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Uncertain
DEOGEN2
Benign
T;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;.;T
M_CAP
Benign
T
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;.;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N
REVEL
Benign
Sift
Uncertain
D;D;D
Sift4G
Benign
T;T;T
Polyphen
B;.;.
Vest4
MutPred
Gain of relative solvent accessibility (P = 0.0082);.;.;
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at