Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

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. 13/22 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 Uncertain significance.

Frequency

Genomes: 𝑓 0.00074 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0014 ( 2 hom. )

Consequence

LHX3
NM_178138.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2

Conservation

PhyloP100: 3.81

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

non-acquired combined pituitary hormone deficiency with spine abnormalities
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
hypothyroidism due to deficient transcription factors involved in pituitary development or function
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

LHX3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014613599).

BP6

Variant 9-136197599-C-G is Benign according to our data. Variant chr9-136197599-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 279837.

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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178138.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LHX3	NM_178138.6	MANE Select	c.920G>C	p.Arg307Pro	missense	Exon 6 of 6	NP_835258.1
LHX3	NM_014564.5		c.935G>C	p.Arg312Pro	missense	Exon 6 of 6	NP_055379.1
LHX3	NM_001363746.1		c.887G>C	p.Arg296Pro	missense	Exon 6 of 6	NP_001350675.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LHX3	ENST00000371748.10	TSL:1 MANE Select	c.920G>C	p.Arg307Pro	missense	Exon 6 of 6	ENSP00000360813.4
LHX3	ENST00000371746.9	TSL:1	c.935G>C	p.Arg312Pro	missense	Exon 6 of 6	ENSP00000360811.3
LHX3	ENST00000619587.1	TSL:1	c.887G>C	p.Arg296Pro	missense	Exon 6 of 6	ENSP00000483080.1

Frequencies

GnomAD3 genomes

AF:

0.000743

AC:

113

AN:

152104

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.000652

AC:

AN:

151868

AF XY:

0.000557

show subpopulations

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 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.:

Cov.:

AF XY:

0.00145

AC XY:

998

AN XY:

687896

show subpopulations

African (AFR)

AF:

0.000126

AC:

AN:

31822

American (AMR)

AF:

0.000790

AC:

AN:

36690

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25020

East Asian (EAS)

AF:

0.00

AC:

AN:

36218

South Asian (SAS)

AF:

0.00

AC:

AN:

79854

European-Finnish (FIN)

AF:

0.0000220

AC:

AN:

45406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5162

European-Non Finnish (NFE)

AF:

0.00179

AC:

1932

AN:

1078114

Other (OTH)

AF:

0.000952

AC:

AN:

57800

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

107

214

322

429

536

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

152

228

304

380

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000742

AC:

113

AN:

152222

Hom.:

Cov.:

AF XY:

0.000645

AC XY:

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41520

American (AMR)

AF:

0.000653

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00140

AC:

AN:

67986

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000672

Hom.:

Bravo

AF:

0.000718

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00108

AC:

ExAC

AF:

0.000321

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Non-acquired combined pituitary hormone deficiency with spine abnormalities (2)

not provided (2)

Combined pituitary hormone deficiencies, genetic form (1)

LHX3-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Benign

0.60

DEOGEN2

Benign

0.21

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.84

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.74

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.015

MetaSVM

Benign

-0.75

MutationAssessor

Benign

1.2

PhyloP100

3.8

PrimateAI

Benign

0.44

PROVEAN

Benign

0.76

REVEL

Uncertain

0.31

Sift

Benign

0.51

Sift4G

Benign

0.31

Polyphen

0.0010

Vest4

0.28

MVP

0.79

MPC

0.012

ClinPred

0.015

GERP RS

0.99

Varity_R

0.13

gMVP

0.46

Mutation Taster

=71/29

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs182345541

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over