rs375579333

Positions:

chr9-136203032-G-A

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

Genomes: 𝑓 0.00085 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0013 ( 1 hom. )

Consequence

LHX3
ENST00000371746.9 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:3

Conservation

PhyloP100: 2.17

Variant links:

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]

LHX3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

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.

BP6

Variant 9-136203032-G-A is Benign according to our data. Variant chr9-136203032-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 279836.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=2}. Variant chr9-136203032-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000848 (129/152196) while in subpopulation NFE AF= 0.0016 (109/67978). AF 95% confidence interval is 0.00136. There are 0 homozygotes in gnomad4. There are 57 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LHX3	NM_178138.6 linkuse as main transcript	c.79+1902C>T		intron_variant		ENST00000371748.10
LHX3	NM_014564.5 linkuse as main transcript	c.8C>T	p.Ala3Val	missense_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LHX3	ENST00000371746.9 linkuse as main transcript	c.8C>T	p.Ala3Val	missense_variant	1/6	1		P1	Q9UBR4-2
LHX3	ENST00000371748.10 linkuse as main transcript	c.79+1902C>T		intron_variant		1	NM_178138.6		Q9UBR4-1
LHX3	ENST00000645419.1 linkuse as main transcript	n.117C>T		non_coding_transcript_exon_variant	1/5

Frequencies

GnomAD3 genomes

AF:

0.000855

AC:

130

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00160

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000810

AC:

AN:

116002

Hom.:

AF XY:

0.000856

AC XY:

AN XY:

64218

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.000690

Gnomad ASJ exome

AF:

0.000917

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000570

Gnomad FIN exome

AF:

0.000573

Gnomad NFE exome

AF:

0.00118

Gnomad OTH exome

AF:

0.000820

GnomAD4 exome

AF:

0.00133

AC:

1824

AN:

1367384

Hom.:

Cov.:

AF XY:

0.00131

AC XY:

884

AN XY:

674638

show subpopulations

Gnomad4 AFR exome

AF:

0.0000699

Gnomad4 AMR exome

AF:

0.000609

Gnomad4 ASJ exome

AF:

0.000650

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000643

Gnomad4 FIN exome

AF:

0.000630

Gnomad4 NFE exome

AF:

0.00153

Gnomad4 OTH exome

AF:

0.00133

GnomAD4 genome

AF:

0.000848

AC:

129

AN:

152196

Hom.:

Cov.:

AF XY:

0.000766

AC XY:

AN XY:

74410

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.00160

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00108

Hom.:

Bravo

AF:

0.000680

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000987

AC:

ExAC

AF:

0.000433

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Pathogenic

1.0

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.60

MetaRNN

Benign

0.0071

MetaSVM

Uncertain

0.11

MutationTaster

Benign

1.0

D;N

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-0.27

REVEL

Uncertain

0.31

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.15

MVP

0.88

MPC

1.9

ClinPred

0.17

GERP RS

3.4

gMVP

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.58

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.58

Position offset: 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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over