rs375579333
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM2PP3BP6BS1
The ENST00000371746.9(LHX3):c.8C>T(p.Ala3Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00129 in 1,519,580 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A3A) has been classified as Likely benign.
Frequency
Consequence
ENST00000371746.9 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LHX3 | NM_178138.6 | c.79+1902C>T | intron_variant | ENST00000371748.10 | |||
LHX3 | NM_014564.5 | c.8C>T | p.Ala3Val | missense_variant | 1/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LHX3 | ENST00000371746.9 | c.8C>T | p.Ala3Val | missense_variant | 1/6 | 1 | P1 | ||
LHX3 | ENST00000371748.10 | c.79+1902C>T | intron_variant | 1 | NM_178138.6 | ||||
LHX3 | ENST00000645419.1 | n.117C>T | non_coding_transcript_exon_variant | 1/5 |
Frequencies
GnomAD3 genomes ? AF: 0.000855 AC: 130AN: 152088Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000810 AC: 94AN: 116002Hom.: 2 AF XY: 0.000856 AC XY: 55AN XY: 64218
GnomAD4 exome AF: 0.00133 AC: 1824AN: 1367384Hom.: 1 Cov.: 35 AF XY: 0.00131 AC XY: 884AN XY: 674638
GnomAD4 genome ? AF: 0.000848 AC: 129AN: 152196Hom.: 0 Cov.: 33 AF XY: 0.000766 AC XY: 57AN XY: 74410
ClinVar
Submissions by phenotype
Non-acquired combined pituitary hormone deficiency with spine abnormalities Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 31, 2022 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 3 of the LHX3 protein (p.Ala3Val). This variant is present in population databases (rs375579333, gnomAD 0.1%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with LHX3-related conditions. ClinVar contains an entry for this variant (Variation ID: 279836). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 26, 2018 | - - |
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 25, 2024 | Variant summary: LHX3 c.8C>T (p.Ala3Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0013 in 1519580 control chromosomes, predominantly at a frequency of 0.0015 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database (v4.0.0) is higher than the estimated maximal expected allele frequency for a pathogenic variant in LHX3 causing Combined Pituitary Hormone Deficiency phenotype (0.0013), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.8C>T in individuals affected with Combined Pituitary Hormone Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 279836). Based on the evidence outlined above, the variant was classified as likely benign. - |
Likely benign, no assertion criteria provided | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 19, 2022 | - - |
Combined pituitary hormone deficiencies, genetic form Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 17, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at