rs137854503

chr9-136198798-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_178138.6(LHX3):c.629C>T(p.Ala210Val) variant causes a missense change involving the alteration of a conserved nucleotide. 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: 33)
• Consequence: LHX3 NM_178138.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.67

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 7 ACMG points.

• PM1: In a DNA_binding_region Homeobox (size 59) in uniprot entity LHX3_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_178138.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.934
• PP5: Variant 9-136198798-G-A is Pathogenic according to our data. Variant chr9-136198798-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 9024.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LHX3	NM_178138.6	c.629C>T	p.Ala210Val	missense_variant	5/6	ENST00000371748.10
LHX3	NM_014564.5	c.644C>T	p.Ala215Val	missense_variant	5/6
LHX3	NM_001363746.1	c.596C>T	p.Ala199Val	missense_variant	5/6
LHX3	XM_017015168.1	c.557C>T	p.Ala186Val	missense_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LHX3	ENST00000371748.10	c.629C>T	p.Ala210Val	missense_variant	5/6	1	NM_178138.6
LHX3	ENST00000371746.9	c.644C>T	p.Ala215Val	missense_variant	5/6	1		P1
LHX3	ENST00000619587.1	c.596C>T	p.Ala199Val	missense_variant	5/6	1
LHX3	ENST00000645419.1	n.1454C>T		non_coding_transcript_exon_variant	4/5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

May 01, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.7	D;D;.
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	D;D;.
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.66
MutPred		0.83		.;Gain of methylation at K211 (P = 0.0378);.;
MVP		0.98
MPC		1.9
ClinPred		0.99	D
GERP RS		2.7
Varity_R		0.87
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs137854503; hg19: chr9-139090644;