rs587776712

chr9-136200736-CA-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_178138.6(LHX3):c.96del(p.Gly33AlafsTer140) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: LHX3 NM_178138.6 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -1.53

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 23 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-136200736-CA-C is Pathogenic according to our data. Variant chr9-136200736-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 9023.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr9-136200736-CA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LHX3	NM_178138.6	c.96del	p.Gly33AlafsTer140	frameshift_variant	2/6	ENST00000371748.10
LHX3	NM_014564.5	c.111del	p.Gly38AlafsTer140	frameshift_variant	2/6
LHX3	NM_001363746.1	c.63del	p.Gly22AlafsTer140	frameshift_variant	2/6
LHX3	XM_017015168.1	c.24del	p.Gly9AlafsTer140	frameshift_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LHX3	ENST00000371748.10	c.96del	p.Gly33AlafsTer140	frameshift_variant	2/6	1	NM_178138.6
LHX3	ENST00000371746.9	c.111del	p.Gly38AlafsTer140	frameshift_variant	2/6	1		P1
LHX3	ENST00000619587.1	c.63del	p.Gly22AlafsTer140	frameshift_variant	2/6	1
LHX3	ENST00000645419.1	n.220del		non_coding_transcript_exon_variant	2/5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2006

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs587776712; hg19: chr9-139092582;