chr1-225937512-G-T
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP5BS2
The NM_003240.5(LEFTY2):c.1030C>A(p.Pro344Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,613,918 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000036 ( 0 hom. )
Consequence
LEFTY2
NM_003240.5 missense
NM_003240.5 missense
Scores
4
7
6
Clinical Significance
Conservation
PhyloP100: 7.70
Genes affected
LEFTY2 (HGNC:3122): (left-right determination factor 2) This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate the mature protein, which plays a role in left-right asymmetry determination of organ systems during development. The protein may also play a role in endometrial bleeding. Mutations in this gene have been associated with left-right axis malformations, particularly in the heart and lungs. Some types of infertility have been associated with dysregulated expression of this gene in the endometrium. This gene is closely linked to both a related family member and a related pseudogene. This gene encodes multiple isoforms that may undergo similar proteolytic processing. [provided by RefSeq, Aug 2016]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PP5
?
Variant 1-225937512-G-T is Pathogenic according to our data. Variant chr1-225937512-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 418283.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
BS2
?
High AC in GnomAdExome at 7 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LEFTY2 | NM_003240.5 | c.1030C>A | p.Pro344Thr | missense_variant | 4/4 | ENST00000366820.10 | |
LEFTY2 | NM_001172425.3 | c.928C>A | p.Pro310Thr | missense_variant | 5/5 | ||
LEFTY2 | XM_011544266.2 | c.*403C>A | 3_prime_UTR_variant | 4/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LEFTY2 | ENST00000366820.10 | c.1030C>A | p.Pro344Thr | missense_variant | 4/4 | 1 | NM_003240.5 | P1 | |
ENST00000513672.1 | n.46C>A | non_coding_transcript_exon_variant | 1/2 | 2 | |||||
LEFTY2 | ENST00000420304.6 | c.928C>A | p.Pro310Thr | missense_variant | 5/5 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152206Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000279 AC: 7AN: 251254Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135874
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 21, 2013 | The Pro344Thr variant in the LEFTY2 gene has not been reported as a pathogenic variant or as a benign polymorphism to our knowledge. Pro344Thr results in a non-conservative amino acid substitution of a non polar, sterically constrained Proline with a polar Threonine at a position that is conserved in mammals. In silico analysis predicts Pro344Thr is damaging to the protein structure/function. Furthermore, the Pro344Thr variant was not observed in external variant databases, indicating it is not a common benign variant in the general population. In summary, Pro344Thr is a good candidate for a pathogenic variant. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D
MetaSVM
Uncertain
T
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Benign
T;T
Polyphen
1.0
.;D
Vest4
MutPred
0.68
.;Gain of MoRF binding (P = 0.0473);
MVP
MPC
0.79
ClinPred
D
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