Genetic Variant LHX3:p.Ala3Gly (chr9-136203032-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The ENST00000371746.9(LHX3):c.8C>G(p.Ala3Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000731 in 1,367,382 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A3V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

LHX3
ENST00000371746.9 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.17

Publications

0 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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.4112885).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LHX3	NM_178138.6 link	c.79+1902C>G		intron_variant	Intron 1 of 5	ENST00000371748.10	NP_835258.1	Q9UBR4-1F1T0D5
LHX3	NM_014564.5 link	c.8C>G	p.Ala3Gly	missense_variant	Exon 1 of 6		NP_055379.1	Q9UBR4-2F1T0D9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LHX3	ENST00000371746.9 link	c.8C>G	p.Ala3Gly	missense_variant	Exon 1 of 6	1		ENSP00000360811.3	Q9UBR4-2
LHX3	ENST00000371748.10 link	c.79+1902C>G		intron_variant	Intron 1 of 5	1	NM_178138.6	ENSP00000360813.4	Q9UBR4-1
LHX3	ENST00000645419.1 link	n.117C>G		non_coding_transcript_exon_variant	Exon 1 of 5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.31e-7

AC:

AN:

1367382

Hom.:

Cov.:

AF XY:

0.00000148

AC XY:

AN XY:

674638

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28598

American (AMR)

AF:

0.00

AC:

AN:

34466

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24610

East Asian (EAS)

AF:

0.00

AC:

AN:

34082

South Asian (SAS)

AF:

0.00

AC:

AN:

77788

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33354

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4748

European-Non Finnish (NFE)

AF:

9.32e-7

AC:

AN:

1072682

Other (OTH)

AF:

0.00

AC:

AN:

57054

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.026

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.21

Eigen_PC

Benign

0.21

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.49

M_CAP

Pathogenic

0.98

MetaRNN

Benign

0.41

MetaSVM

Uncertain

0.033

PhyloP100

2.2

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.31

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.16

MutPred

0.32

Loss of relative solvent accessibility (P = 0.0186);

MVP

0.87

MPC

1.9

ClinPred

0.98

GERP RS

3.4

PromoterAI

-0.055

Neutral

(source)

gMVP

0.44

Mutation Taster

=88/12

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over