rs104894117

chr9-136199800-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 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

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a domain LIM zinc-binding 2 (size 54) in uniprot entity LHX3_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_178138.6
• 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 id is 9021.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr9-136199800-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LHX3	NM_178138.6	c.332A>G	p.Tyr111Cys	missense_variant	3/6	ENST00000371748.10
LHX3	NM_014564.5	c.347A>G	p.Tyr116Cys	missense_variant	3/6
LHX3	NM_001363746.1	c.299A>G	p.Tyr100Cys	missense_variant	3/6
LHX3	XM_017015168.1	c.260A>G	p.Tyr87Cys	missense_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LHX3	ENST00000371748.10	c.332A>G	p.Tyr111Cys	missense_variant	3/6	1	NM_178138.6
LHX3	ENST00000371746.9	c.347A>G	p.Tyr116Cys	missense_variant	3/6	1		P1
LHX3	ENST00000619587.1	c.299A>G	p.Tyr100Cys	missense_variant	3/6	1
LHX3	ENST00000645419.1	n.1157A>G		non_coding_transcript_exon_variant	2/5

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 35

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

Jul 15, 2008

- -

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
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
MutationTaster	Benign	1.0	A;A
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs104894117; hg19: chr9-139091646;