1-165204029-G-C

Variant names:

• chr1-165204029-G-C
• NM_177398.4:c.1000C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_177398.4(LMX1A):​c.1000C>G​(p.Leu334Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: LMX1A NM_177398.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.70

Genes affected

LMX1A (HGNC:6653): (LIM homeobox transcription factor 1 alpha) This gene encodes a homeodomain and LIM-domain containing protein. The encoded protein is a transcription factor that acts as a positive regulator of insulin gene transcription. This gene also plays a role in the development of dopamine producing neurons during embryogenesis. Mutations in this gene are associated with an increased risk of developing Parkinson's disease. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Feb 2012]

LMX1A-AS2 (HGNC:40343): (LMX1A antisense RNA 2)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1233992).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMX1A	NM_177398.4	c.1000C>G	p.Leu334Val	missense_variant	Exon 9 of 9	ENST00000342310.7	NP_796372.1
LMX1A	NM_001174069.2	c.1000C>G	p.Leu334Val	missense_variant	Exon 9 of 9		NP_001167540.1
LMX1A	XM_011509538.4	c.760C>G	p.Leu254Val	missense_variant	Exon 7 of 7		XP_011507840.1
LMX1A-AS2	XR_922234.2	n.-18G>C		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LMX1A	ENST00000342310.7	c.1000C>G	p.Leu334Val	missense_variant	Exon 9 of 9	2	NM_177398.4	ENSP00000340226.3
LMX1A	ENST00000367893.4	c.1000C>G	p.Leu334Val	missense_variant	Exon 8 of 8	1		ENSP00000356868.4
LMX1A	ENST00000489443.2	n.634C>G		non_coding_transcript_exon_variant	Exon 7 of 7	1
LMX1A	ENST00000294816.6	c.1000C>G	p.Leu334Val	missense_variant	Exon 9 of 9	2		ENSP00000294816.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1000C>G (p.L334V) alteration is located in exon 9 (coding exon 8) of the LMX1A gene. This alteration results from a C to G substitution at nucleotide position 1000, causing the leucine (L) at amino acid position 334 to be replaced by a valine (V). 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	Benign	0.078
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	21
DANN	Uncertain	0.97
DEOGEN2	Benign	0.28	T;T;T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.072
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.87	.;.;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	1.1	L;L;L
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.24	N;N;N
REVEL	Uncertain	0.37
Sift	Benign	0.65	T;T;T
Sift4G	Benign	0.50	T;T;T
Polyphen		0.065	B;B;B
Vest4		0.069
MutPred		0.32		Loss of stability (P = 0.1835);Loss of stability (P = 0.1835);Loss of stability (P = 0.1835);
MVP		0.38
MPC		0.26
ClinPred		0.66	D
GERP RS		5.1
Varity_R		0.22
gMVP		0.19

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: chr1-165173266;