chr5-141644412-A-C
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_033449.3(FCHSD1):c.1669T>G(p.Tyr557Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,613,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000011 ( 0 hom. )
Consequence
FCHSD1
NM_033449.3 missense
NM_033449.3 missense
Scores
11
6
2
Clinical Significance
Conservation
PhyloP100: 8.91
Genes affected
FCHSD1 (HGNC:25463): (FCH and double SH3 domains 1) Predicted to enable lipid binding activity. Predicted to be involved in neuromuscular synaptic transmission and positive regulation of actin filament polymerization. Predicted to be located in cell projection and perikaryon. Predicted to be active in neuromuscular junction and recycling endosome. Predicted to colocalize with cuticular plate. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.958
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FCHSD1 | NM_033449.3 | c.1669T>G | p.Tyr557Asp | missense_variant | 17/20 | ENST00000435817.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FCHSD1 | ENST00000435817.7 | c.1669T>G | p.Tyr557Asp | missense_variant | 17/20 | 1 | NM_033449.3 | P1 | |
FCHSD1 | ENST00000522783.5 | c.1447T>G | p.Tyr483Asp | missense_variant | 16/20 | 5 | |||
FCHSD1 | ENST00000523856.5 | n.1338T>G | non_coding_transcript_exon_variant | 8/11 | 2 | ||||
FCHSD1 | ENST00000522126.5 | c.*207T>G | 3_prime_UTR_variant, NMD_transcript_variant | 16/19 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152136Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000322 AC: 8AN: 248710Hom.: 0 AF XY: 0.0000370 AC XY: 5AN XY: 134968
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GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461582Hom.: 0 Cov.: 33 AF XY: 0.0000179 AC XY: 13AN XY: 727072
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GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152136Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74324
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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 | Nov 30, 2022 | The c.1669T>G (p.Y557D) alteration is located in exon 17 (coding exon 17) of the FCHSD1 gene. This alteration results from a T to G substitution at nucleotide position 1669, causing the tyrosine (Y) at amino acid position 557 to be replaced by an aspartic acid (D). 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
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Benign
T;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;T
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D
Sift4G
Uncertain
D;D
Polyphen
D;.
Vest4
MutPred
Gain of disorder (P = 0.0126);.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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