chr9-136199800-T-C

Variant names:

• chr9-136199800-T-C
• rs104894117
• NM_178138.6:c.332A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_178138.6(LHX3):​c.332A>G​(p.Tyr111Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 35)
• Consequence: LHX3 NM_178138.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.86
• Publications: 7 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 9-136199800-T-C is Pathogenic according to our data. Variant chr9-136199800-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 9021.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.332A>G	p.Tyr111Cys	missense_variant	Exon 3 of 6	ENST00000371748.10	NP_835258.1
LHX3	NM_014564.5	c.347A>G	p.Tyr116Cys	missense_variant	Exon 3 of 6		NP_055379.1
LHX3	NM_001363746.1	c.299A>G	p.Tyr100Cys	missense_variant	Exon 3 of 6		NP_001350675.1
LHX3	XM_017015168.1	c.260A>G	p.Tyr87Cys	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.332A>G	p.Tyr111Cys	missense_variant	Exon 3 of 6	1	NM_178138.6	ENSP00000360813.4
LHX3	ENST00000371746.9	c.347A>G	p.Tyr116Cys	missense_variant	Exon 3 of 6	1		ENSP00000360811.3
LHX3	ENST00000619587.1	c.299A>G	p.Tyr100Cys	missense_variant	Exon 3 of 6	1		ENSP00000483080.1
LHX3	ENST00000645419.1	n.1157A>G		non_coding_transcript_exon_variant	Exon 2 of 5

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 35

Alfa AF: 0.00 Hom.: 0

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

Jul 15, 2008

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
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	.;D;.
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	.;H;.
PhyloP100		4.9
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-8.2	D;D;.
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.95
MutPred		0.86		.;Gain of loop (P = 0.0312);.;
MVP		0.98
MPC		2.1
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.98
gMVP		0.82
Mutation Taster		=11/89	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs104894117; hg19: chr9-139091646;