chr9-136203032-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP3BP6BS1

The NM_014564.5(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
NM_014564.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.17

Publications

2 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
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: Likely_benign. The variant received -4 ACMG points.

PP3

Splicing predictors support a deleterious 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 VariationId is 279836.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014564.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LHX3	NM_178138.6	MANE Select	c.79+1902C>T		intron	N/A	NP_835258.1	Q9UBR4-1
	LHX3	NM_014564.5		c.8C>T	p.Ala3Val	missense	Exon 1 of 6	NP_055379.1	Q9UBR4-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LHX3	ENST00000371746.9	TSL:1	c.8C>T	p.Ala3Val	missense	Exon 1 of 6	ENSP00000360811.3	Q9UBR4-2
LHX3	ENST00000371748.10	TSL:1 MANE Select	c.79+1902C>T		intron	N/A	ENSP00000360813.4	Q9UBR4-1
LHX3	ENST00000645419.1		n.117C>T		non_coding_transcript_exon	Exon 1 of 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

GnomAD2 exomes

AF:

0.000810

AC:

AN:

116002

AF XY:

0.000856

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 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

African (AFR)

AF:

0.0000699

AC:

AN:

28598

American (AMR)

AF:

0.000609

AC:

AN:

34466

Ashkenazi Jewish (ASJ)

AF:

0.000650

AC:

AN:

24610

East Asian (EAS)

AF:

0.00

AC:

AN:

34082

South Asian (SAS)

AF:

0.000643

AC:

AN:

77788

European-Finnish (FIN)

AF:

0.000630

AC:

AN:

33354

Middle Eastern (MID)

AF:

0.000421

AC:

AN:

4748

European-Non Finnish (NFE)

AF:

0.00153

AC:

1636

AN:

1072684

Other (OTH)

AF:

0.00133

AC:

AN:

57054

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

100

199

299

398

498

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

180

240

300

<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:

0.000848

AC:

129

AN:

152196

Hom.:

Cov.:

AF XY:

0.000766

AC XY:

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.000169

AC:

AN:

41542

American (AMR)

AF:

0.000131

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00124

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00160

AC:

109

AN:

67978

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

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:

0.00108

Hom.:

Bravo

AF:

0.000680

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000987

AC:

ExAC

AF:

0.000433

AC:

ClinVar

ClinVar submissions

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)

not specified (2)

Combined pituitary hormone deficiencies, genetic form (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

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

PhyloP100

2.2

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

PromoterAI

0.053

Neutral

(source)

gMVP

0.49

Mutation Taster

=95/5

polymorphism

(source)

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

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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

Computational scores

Splicing

Publications

Other links and lift over