1-180271378-A-C
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PM2PP3_ModeratePP5_Moderate
The NM_033343.4(LHX4):c.452-2A>C variant causes a splice acceptor change. The variant allele was found at a frequency of 0.0000031 in 1,614,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
LHX4
NM_033343.4 splice_acceptor
NM_033343.4 splice_acceptor
Scores
3
1
3
Clinical Significance
Conservation
PhyloP100: 7.03
Genes affected
LHX4 (HGNC:21734): (LIM homeobox 4) This gene encodes a member of a large protein family which contains the LIM domain, a unique cysteine-rich zinc-binding domain. The encoded protein is a transcription factor involved in the control of differentiation and development of the pituitary gland. Mutations in this gene cause combined pituitary hormone deficiency 4. [provided by RefSeq, Dec 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
?
Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
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Variant 1-180271378-A-C is Pathogenic according to our data. Variant chr1-180271378-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 189234.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LHX4 | NM_033343.4 | c.452-2A>C | splice_acceptor_variant | ENST00000263726.4 | |||
LHX4-AS1 | NR_037642.1 | n.942T>G | non_coding_transcript_exon_variant | 5/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LHX4 | ENST00000263726.4 | c.452-2A>C | splice_acceptor_variant | 1 | NM_033343.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152230Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461882Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727242
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152230Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74378
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Short stature-pituitary and cerebellar defects-small sella turcica syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 27, 2014 | The c.452-2A>C variant in LHX4 has not been reported in individuals with combined pituitary hormone deficiency (CPHD) or in large population studies. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function variants in the heterozygous state, and in particular splice variants, have been reported in individuals with CPHD (reviewed by Tajima et al., 2013). In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Benign
Cadd
Pathogenic
Dann
Benign
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 11
DS_AL_spliceai
Position offset: 2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at