9-136203032-G-C

Variant names:

• chr9-136203032-G-C
• rs375579333
• ENST00000371746.9:c.8C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.17
• Publications: 0 publications found

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

ACMG classification

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).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000371746.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LHX3	NM_178138.6	MANE Select	c.79+1902C>G		intron	N/A	NP_835258.1
	LHX3	NM_014564.5		c.8C>G	p.Ala3Gly	missense	Exon 1 of 6	NP_055379.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LHX3	ENST00000371746.9	TSL:1	c.8C>G	p.Ala3Gly	missense	Exon 1 of 6	ENSP00000360811.3
	LHX3	ENST00000371748.10	TSL:1 MANE Select	c.79+1902C>G		intron	N/A	ENSP00000360813.4
	LHX3	ENST00000645419.1		n.117C>G		non_coding_transcript_exon	Exon 1 of 5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.31e-7 AC: 1 AN: 1367382 Hom.: 0 Cov.: 35 AF XY: 0.00000148 AC XY: 1 AN XY: 674638

African (AFR) AF: 0.00 AC: 0 AN: 28598

American (AMR) AF: 0.00 AC: 0 AN: 34466

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24610

East Asian (EAS) AF: 0.00 AC: 0 AN: 34082

South Asian (SAS) AF: 0.00 AC: 0 AN: 77788

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33354

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4748

European-Non Finnish (NFE) AF: 9.32e-7 AC: 1 AN: 1072682

Other (OTH) AF: 0.00 AC: 0 AN: 57054

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	19
DANN	Uncertain	1.0
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.49	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.41	T
MetaSVM	Uncertain	0.033	D
PhyloP100		2.2
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.31
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.16
MutPred		0.32		Loss of relative solvent accessibility (P = 0.0186)
MVP		0.87
MPC		1.9
ClinPred		0.98	D
GERP RS		3.4
PromoterAI		-0.055	Neutral
gMVP		0.44
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs375579333; hg19: chr9-139094878;