1-197921567-C-T

Position:

• chr1-197921567-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_020204.3(LHX9):​c.641C>T​(p.Pro214Leu) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LHX9 NM_020204.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57

Genes affected

LHX9 (HGNC:14222): (LIM homeobox 9) This gene encodes a member of the LIM homeobox gene family of developmentally expressed transcription factors. The encoded protein contains a homeodomain and two cysteine-rich zinc-binding LIM domains involved in protein-protein interactions. The protein is highly similar to a mouse protein that causes gonadal agenesis when inactivated, suggesting a role in gonadal development. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.846

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LHX9	NM_020204.3	c.641C>T	p.Pro214Leu	missense_variant	3/5	ENST00000367387.6	NP_064589.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LHX9	ENST00000367387.6	c.641C>T	p.Pro214Leu	missense_variant	3/5	1	NM_020204.3	ENSP00000356357.4
LHX9	ENST00000367390.7	c.614C>T	p.Pro205Leu	missense_variant	4/6	1		ENSP00000356360.3
LHX9	ENST00000561173.5	c.659C>T	p.Pro220Leu	missense_variant	4/6	5		ENSP00000453064.1
LHX9	ENST00000367391.5	c.614C>T	p.Pro205Leu	missense_variant	4/6	5		ENSP00000356361.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 03, 2022

The c.641C>T (p.P214L) alteration is located in exon 3 (coding exon 3) of the LHX9 gene. This alteration results from a C to T substitution at nucleotide position 641, causing the proline (P) at amino acid position 214 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.77	.;.;.;D
Eigen	Benign	0.12
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.85	D;D;D;D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Uncertain	2.1	.;.;.;M
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-4.6	D;D;D;D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.012	D;D;D;D
Polyphen		0.70	P;B;.;P
Vest4		0.92
MutPred		0.47		.;.;.;Gain of MoRF binding (P = 0.0891);
MVP		0.98
MPC		0.65
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.30
gMVP		0.56

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: chr1-197890697;