9-124015235-G-A

Variant names:

• chr9-124015235-G-A
• NM_004789.4:c.437G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_004789.4(LHX2):​c.437G>A​(p.Cys146Tyr) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LHX2 NM_004789.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 10.0

Genes affected

LHX2 (HGNC:6594): (LIM homeobox 2) This gene encodes a protein belonging to a large protein family, members of which carry the LIM domain, a unique cysteine-rich zinc-binding domain. The encoded protein may function as a transcriptional regulator. The protein can recapitulate or rescue phenotypes in Drosophila caused by a related protein, suggesting conservation of function during evolution. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 9-124015235-G-A is Pathogenic according to our data. Variant chr9-124015235-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 3340939.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-124015235-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LHX2	NM_004789.4	c.437G>A	p.Cys146Tyr	missense_variant	Exon 3 of 5	ENST00000373615.9	NP_004780.3
LHX2	XM_006717323.4	c.437G>A	p.Cys146Tyr	missense_variant	Exon 3 of 6		XP_006717386.1
LHX2	XM_047424082.1	c.437G>A	p.Cys146Tyr	missense_variant	Exon 3 of 6		XP_047280038.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LHX2	ENST00000373615.9	c.437G>A	p.Cys146Tyr	missense_variant	Exon 3 of 5	1	NM_004789.4	ENSP00000362717.4
LHX2	ENST00000446480.5	c.452G>A	p.Cys151Tyr	missense_variant	Exon 3 of 5	2		ENSP00000394978.1
LHX2	ENST00000560961.2	c.314G>A	p.Cys105Tyr	missense_variant	Exon 3 of 3	3		ENSP00000453448.3
LHX2	ENST00000488674.2	c.-164G>A		upstream_gene_variant		3		ENSP00000476200.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Aug 07, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect with impaired transactivation (Schmid CM et al., 2023); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 37057675) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	.;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	5.0	.;H
PrimateAI	Pathogenic	0.97	D
PROVEAN	Pathogenic	-11	D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	.;D
Vest4		0.94
MutPred		0.85		.;Gain of helix (P = 0.0854);
MVP		0.98
MPC		2.9
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.97
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-126777514;