4-73495309-T-G
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_001133.2(AFM):c.1068T>G(p.Phe356Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000234 in 1,579,676 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000022 ( 0 hom. )
Consequence
AFM
NM_001133.2 missense
NM_001133.2 missense
Scores
1
6
12
Clinical Significance
Conservation
PhyloP100: 1.31
Genes affected
AFM (HGNC:316): (afamin) This gene is a member of the albumin gene family, which is comprised of four genes that localize to chromosome 4 in a tandem arrangement. These four genes encode structurally-related serum transport proteins that are known to be evolutionarily related. The protein encoded by this gene is regulated developmentally, expressed in the liver and secreted into the bloodstream. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AFM | NM_001133.2 | c.1068T>G | p.Phe356Leu | missense_variant | 9/15 | ENST00000226355.5 | |
AFM | XM_017007842.3 | c.1068T>G | p.Phe356Leu | missense_variant | 9/13 | ||
AFM | XM_017007843.3 | c.1068T>G | p.Phe356Leu | missense_variant | 9/11 | ||
AFM | XM_017007844.3 | c.1068T>G | p.Phe356Leu | missense_variant | 9/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AFM | ENST00000226355.5 | c.1068T>G | p.Phe356Leu | missense_variant | 9/15 | 1 | NM_001133.2 | P1 | |
AFM | ENST00000505794.1 | n.195T>G | non_coding_transcript_exon_variant | 1/2 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000328 AC: 5AN: 152226Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000133 AC: 29AN: 218550Hom.: 0 AF XY: 0.0000756 AC XY: 9AN XY: 119008
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GnomAD4 exome AF: 0.0000224 AC: 32AN: 1427450Hom.: 0 Cov.: 30 AF XY: 0.0000113 AC XY: 8AN XY: 709636
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GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152226Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5AN XY: 74368
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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 | Apr 22, 2022 | The c.1068T>G (p.F356L) alteration is located in exon 9 (coding exon 9) of the AFM gene. This alteration results from a T to G substitution at nucleotide position 1068, causing the phenylalanine (F) at amino acid position 356 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
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
M_CAP
Benign
D
MetaRNN
Uncertain
T
MetaSVM
Benign
T
MutationAssessor
Benign
L
MutationTaster
Benign
N
PrimateAI
Benign
T
PROVEAN
Uncertain
D
REVEL
Benign
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
B
Vest4
MutPred
Gain of glycosylation at S359 (P = 0.0271);
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