9-136203031-CG-GA

Variant names:

• chr9-136203031-CG-GA
• ENST00000371746.9:c.8_9delCGinsTC
• LHX3 p.Ala3Val

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_014564.5(LHX3):​c.8_9delCGinsTC​(p.Ala3Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. A3A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LHX3 NM_014564.5 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: 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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+1902_79+1903delCGinsTC		intron	N/A	NP_835258.1	Q9UBR4-1
	LHX3	NM_014564.5		c.8_9delCGinsTC	p.Ala3Val	missense	N/A	NP_055379.1	Q9UBR4-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LHX3	ENST00000371746.9	TSL:1	c.8_9delCGinsTC	p.Ala3Val	missense	N/A	ENSP00000360811.3	Q9UBR4-2
	LHX3	ENST00000371748.10	TSL:1 MANE Select	c.79+1902_79+1903delCGinsTC		intron	N/A	ENSP00000360813.4	Q9UBR4-1
	LHX3	ENST00000645419.1		n.117_118delCGinsTC		non_coding_transcript_exon	Exon 1 of 5

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.2

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr9-139094877;