rs137854504

Variant names:

• chr9-136199844-GC-AGGA
• rs137854504
• NM_178138.6:c.287_288delGCinsTCCT

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_178138.6(LHX3):​c.287_288delGCinsTCCT​(p.Gly96ValfsTer78) variant causes a frameshift, missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G96S) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 34)
• Consequence: LHX3 NM_178138.6 frameshift, missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.59
• Publications: 3 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: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-136199844-GC-AGGA is Pathogenic according to our data. Variant chr9-136199844-GC-AGGA is described in ClinVar as Pathogenic. ClinVar VariationId is 9025.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LHX3	NM_178138.6	c.287_288delGCinsTCCT	p.Gly96ValfsTer78	frameshift_variant, missense_variant	Exon 3 of 6	ENST00000371748.10	NP_835258.1
LHX3	NM_014564.5	c.302_303delGCinsTCCT	p.Gly101ValfsTer78	frameshift_variant, missense_variant	Exon 3 of 6		NP_055379.1
LHX3	NM_001363746.1	c.254_255delGCinsTCCT	p.Gly85ValfsTer78	frameshift_variant, missense_variant	Exon 3 of 6		NP_001350675.1
LHX3	XM_017015168.1	c.215_216delGCinsTCCT	p.Gly72ValfsTer78	frameshift_variant, missense_variant	Exon 3 of 6		XP_016870657.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LHX3	ENST00000371748.10	c.287_288delGCinsTCCT	p.Gly96ValfsTer78	frameshift_variant, missense_variant	Exon 3 of 6	1	NM_178138.6	ENSP00000360813.4
LHX3	ENST00000371746.9	c.302_303delGCinsTCCT	p.Gly101ValfsTer78	frameshift_variant, missense_variant	Exon 3 of 6	1		ENSP00000360811.3
LHX3	ENST00000619587.1	c.254_255delGCinsTCCT	p.Gly85ValfsTer78	frameshift_variant, missense_variant	Exon 3 of 6	1		ENSP00000483080.1
LHX3	ENST00000645419.1	n.1112_1113delGCinsTCCT		non_coding_transcript_exon_variant	Exon 2 of 5

Frequencies

GnomAD3 genomes Cov.: 34

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

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Non-acquired combined pituitary hormone deficiency with spine abnormalities Pathogenic:1

May 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.6
Mutation Taster		=1/199	disease causing (fs/PTC)

Splicing

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

Other links and lift over

dbSNP: rs137854504; hg19: chr9-139091690;