rs587776711

Positions:

• chr9-136199657-AGCGTCGTCCCCTCGGCTGACCTC-A

Variant summary

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

The NM_178138.6(LHX3):​c.452_454+20del variant causes a splice donor, splice donor 5th base, coding sequence, intron 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: 34)
• Consequence: LHX3 NM_178138.6 splice_donor, splice_donor_5th_base, coding_sequence, intron
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 0.472

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: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-136199657-AGCGTCGTCCCCTCGGCTGACCTC-A is Pathogenic according to our data. Variant chr9-136199657-AGCGTCGTCCCCTCGGCTGACCTC-A is described in ClinVar as [Pathogenic]. Clinvar id is 9022.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr9-136199657-AGCGTCGTCCCCTCGGCTGACCTC-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LHX3	NM_178138.6	c.452_454+20del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	3/6	ENST00000371748.10	NP_835258.1
LHX3	NM_001363746.1	c.419_421+20del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	3/6		NP_001350675.1
LHX3	NM_014564.5	c.467_469+20del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	3/6		NP_055379.1
LHX3	XM_017015168.1	c.380_382+20del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	3/6		XP_016870657.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LHX3	ENST00000371748.10	c.452_454+20del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	3/6	1	NM_178138.6	ENSP00000360813
LHX3	ENST00000371746.9	c.467_469+20del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	3/6	1		ENSP00000360811	P1
LHX3	ENST00000619587.1	c.419_421+20del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	3/6	1		ENSP00000483080
LHX3	ENST00000645419.1	n.1277_1279+20del		splice_donor_variant, splice_donor_5th_base_variant, non_coding_transcript_exon_variant, intron_variant	2/5

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:2

Revision: no assertion criteria provided

Submissions by phenotype

Non-acquired combined pituitary hormone deficiency with spine abnormalities Pathogenic:2

Pathogenic, no assertion criteria provided	curation	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	Dec 30, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 15, 2008	- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs587776711; hg19: chr9-139091503;