chr1-180230530-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PVS1_SupportingPM2

The NM_033343.4(LHX4):ā€‹c.1A>Gā€‹(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000657 in 152,182 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 (no stars).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 31)

Consequence

LHX4
NM_033343.4 start_lost

Scores

5
7
4

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 6.02
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PVS1
Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 3 CDS bases. Genomic position: 180230532. Lost 0.003 part of the original CDS.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LHX4NM_033343.4 linkc.1A>G p.Met1? start_lost Exon 1 of 6 ENST00000263726.4 NP_203129.1 Q969G2A0A0S2Z5S4
LHX4XM_011510105.3 linkc.-108+1617A>G intron_variant Intron 1 of 5 XP_011508407.1
LHX4XM_011510106.4 linkc.-108+1377A>G intron_variant Intron 1 of 5 XP_011508408.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LHX4ENST00000263726.4 linkc.1A>G p.Met1? start_lost Exon 1 of 6 1 NM_033343.4 ENSP00000263726.2 Q969G2
LHX4ENST00000558139.1 linkn.233A>G non_coding_transcript_exon_variant Exon 1 of 2 3

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152182
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
Cov.:
30
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152182
Hom.:
0
Cov.:
31
AF XY:
0.0000135
AC XY:
1
AN XY:
74332
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

LHX4-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesDec 13, 2023The LHX4 c.1A>G variant is predicted to disrupt the translation initiation site (Start loss). To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. This variant impacts a highly conserved base as well as a highly conserved residue in the LHX4 gene. However, the impacted residue is adjacent to another Methionine codon, which may be used as the translation start site in the presence of this variant. Start-loss variants are frequently pathogenic. However, although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.41
D
BayesDel_noAF
Pathogenic
0.36
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.12
T
Eigen
Benign
0.13
Eigen_PC
Uncertain
0.28
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Uncertain
0.90
D
M_CAP
Pathogenic
0.52
D
MetaRNN
Pathogenic
0.81
D
MetaSVM
Uncertain
-0.058
T
PROVEAN
Benign
-0.39
N
REVEL
Uncertain
0.53
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.045
D
Polyphen
0.23
B
Vest4
0.95
MutPred
0.45
Loss of loop (P = 0.1258);
MVP
0.84
ClinPred
1.0
D
GERP RS
5.5
Varity_R
0.79
gMVP
0.49

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.080
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1664150962; hg19: chr1-180199665; API