1-225937476-C-T
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_003240.5(LEFTY2):c.1066G>A(p.Asp356Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000131 in 1,614,094 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 0.00015 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00013 ( 0 hom. )
Consequence
LEFTY2
NM_003240.5 missense
NM_003240.5 missense
Scores
2
8
7
Clinical Significance
Conservation
PhyloP100: 5.84
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 -6 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.16786873).
BS2
?
High AC in GnomAd at 23 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LEFTY2 | NM_003240.5 | c.1066G>A | p.Asp356Asn | missense_variant | 4/4 | ENST00000366820.10 | |
LEFTY2 | NM_001172425.3 | c.964G>A | p.Asp322Asn | missense_variant | 5/5 | ||
LEFTY2 | XM_011544266.2 | c.*439G>A | 3_prime_UTR_variant | 4/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LEFTY2 | ENST00000366820.10 | c.1066G>A | p.Asp356Asn | missense_variant | 4/4 | 1 | NM_003240.5 | P1 | |
ENST00000513672.1 | n.82G>A | non_coding_transcript_exon_variant | 1/2 | 2 | |||||
LEFTY2 | ENST00000420304.6 | c.964G>A | p.Asp322Asn | missense_variant | 5/5 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.000151 AC: 23AN: 152234Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000159 AC: 40AN: 251208Hom.: 0 AF XY: 0.000132 AC XY: 18AN XY: 135860
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GnomAD4 exome AF: 0.000129 AC: 189AN: 1461742Hom.: 0 Cov.: 29 AF XY: 0.000143 AC XY: 104AN XY: 727168
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 19, 2022 | The c.1066G>A (p.D356N) alteration is located in exon 4 (coding exon 4) of the LEFTY2 gene. This alteration results from a G to A substitution at nucleotide position 1066, causing the aspartic acid (D) at amino acid position 356 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Left-right axis malformations Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 10, 2023 | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 356 of the LEFTY2 protein (p.Asp356Asn). This variant is present in population databases (rs543472211, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with LEFTY2-related conditions. ClinVar contains an entry for this variant (Variation ID: 655865). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Pathogenic
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
T
MutationTaster
Benign
D;D
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
0.98
.;D
Vest4
MutPred
0.43
.;Gain of MoRF binding (P = 0.0174);
MVP
MPC
0.64
ClinPred
D
GERP RS
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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