rs182345541

chr9-136197599-C-Gchr9-136197599-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_178138.6(LHX3):c.920G>C(p.Arg307Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00138 in 1,548,308 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict 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. R307R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00074 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (2 hom.)
• Consequence: LHX3 NM_178138.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 3.81

Genes affected

LHX3 (HGNC:6595): (LIM homeobox 3) This gene encodes a member of a large family of proteins which carry the LIM domain, a unique cysteine-rich zinc-binding domain. The encoded protein is a transcription factor that is required for pituitary development and motor neuron specification. Mutations in this gene cause combined pituitary hormone deficiency 3. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2015]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014613599).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000742 (113/152222) while in subpopulation NFE AF= 0.0014 (95/67986). AF 95% confidence interval is 0.00117. There are 0 homozygotes in gnomad4. There are 48 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LHX3	NM_178138.6	c.920G>C	p.Arg307Pro	missense_variant	6/6	ENST00000371748.10
LHX3	NM_014564.5	c.935G>C	p.Arg312Pro	missense_variant	6/6
LHX3	NM_001363746.1	c.887G>C	p.Arg296Pro	missense_variant	6/6
LHX3	XM_017015168.1	c.848G>C	p.Arg283Pro	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LHX3	ENST00000371748.10	c.920G>C	p.Arg307Pro	missense_variant	6/6	1	NM_178138.6
LHX3	ENST00000371746.9	c.935G>C	p.Arg312Pro	missense_variant	6/6	1		P1
LHX3	ENST00000619587.1	c.887G>C	p.Arg296Pro	missense_variant	6/6	1
LHX3	ENST00000645419.1	n.1745G>C		non_coding_transcript_exon_variant	5/5

Frequencies

GnomAD3 genomes AF: 0.000743 AC: 113 AN: 152104 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

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: 0.00140

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000652 AC: 99 AN: 151868 Hom.: 0 AF XY: 0.000557 AC XY: 46 AN XY: 82636

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000818

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000763

Gnomad NFE exome AF: 0.00134

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00145 AC: 2021 AN: 1396086 Hom.: 2 Cov.: 34 AF XY: 0.00145 AC XY: 998 AN XY: 687896

Gnomad4 AFR exome AF: 0.000126

Gnomad4 AMR exome AF: 0.000790

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000220

Gnomad4 NFE exome AF: 0.00179

Gnomad4 OTH exome AF: 0.000952

GnomAD4 genome AF: 0.000742 AC: 113 AN: 152222 Hom.: 0 Cov.: 33 AF XY: 0.000645 AC XY: 48 AN XY: 74420

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00140

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000672 Hom.: 0

Bravo AF: 0.000718

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00108 AC: 9

ExAC AF: 0.000321 AC: 37

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Mar 04, 2022	This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 312 of the LHX3 protein (p.Arg312Pro). This variant is present in population databases (rs182345541, gnomAD 0.1%), 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 LHX3-related conditions. ClinVar contains an entry for this variant (Variation ID: 279837). 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: "Benign"; Align-GVGD: "Not Available"). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 20, 2016	The R312P variant in the LHX3 gene has been reported previously in one individual with pituitary aplasia; however, no second LHX3 variant was identified, and R312P was also present in the heterozygous state in this individual's unaffected father and sister (Sobrier et al., 2006). The R312P variant was not observed at any significant frequency in approximately 6300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R312P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved, and in silico analysis predicts this variant likely does not alter the protein structure/function. We interpret R312P as a variant of uncertain significance. -

Non-acquired combined pituitary hormone deficiency with spine abnormalities Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Likely benign, 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Combined pituitary hormone deficiencies, genetic form Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Dec 24, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.20
Cadd	Benign	14
Dann	Benign	0.60
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.84
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.74	T;T;T
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.015	T;T;T
MetaSVM	Benign	-0.75	T
MutationTaster	Benign	0.91	N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.76	N;N;.
REVEL	Uncertain	0.31
Sift	Benign	0.51	T;T;.
Sift4G	Benign	0.31	T;T;T
Polyphen		0.0010	.;B;.
Vest4		0.28
MVP		0.79
MPC		0.012
ClinPred		0.015	T
GERP RS		0.99
Varity_R		0.13
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs182345541; hg19: chr9-139089445;