1-165206034-G-A

Position:

• chr1-165206034-G-A

Variant summary

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

The NM_177398.4(LMX1A):​c.818C>T​(p.Ala273Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LMX1A NM_177398.4 missense, splice_region
• Scores: Splicing: ADA: 0.01190
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.19

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=0.09795675).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMX1A	NM_177398.4	c.818C>T	p.Ala273Val	missense_variant, splice_region_variant	8/9	ENST00000342310.7	NP_796372.1
LMX1A	NM_001174069.2	c.818C>T	p.Ala273Val	missense_variant, splice_region_variant	8/9		NP_001167540.1
LMX1A	XM_011509538.4	c.578C>T	p.Ala193Val	missense_variant, splice_region_variant	6/7		XP_011507840.1
LMX1A-AS2	XR_922234.2	n.366+264G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMX1A	ENST00000342310.7	c.818C>T	p.Ala273Val	missense_variant, splice_region_variant	8/9	2	NM_177398.4	ENSP00000340226.3
LMX1A	ENST00000367893.4	c.818C>T	p.Ala273Val	missense_variant, splice_region_variant	7/8	1		ENSP00000356868.4
LMX1A	ENST00000489443.2	n.452C>T		splice_region_variant, non_coding_transcript_exon_variant	6/7	1
LMX1A	ENST00000294816.6	c.818C>T	p.Ala273Val	missense_variant, splice_region_variant	8/9	2		ENSP00000294816.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Jan 17, 2024

The c.818C>T (p.A273V) alteration is located in exon 8 (coding exon 7) of the LMX1A gene. This alteration results from a C to T substitution at nucleotide position 818, causing the alanine (A) at amino acid position 273 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	0.070
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T;T;T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.75	.;.;T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.098	T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.26	N;N;N
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.22
Sift	Benign	0.37	T;T;T
Sift4G	Benign	0.29	T;T;T
Polyphen		0.010	B;B;B
Vest4		0.20
MutPred		0.13		Gain of MoRF binding (P = 0.1235);Gain of MoRF binding (P = 0.1235);Gain of MoRF binding (P = 0.1235);
MVP		0.48
MPC		0.25
ClinPred		0.27	T
GERP RS		3.4
Varity_R		0.072
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.012
dbscSNV1_RF	Benign	0.16
SpliceAI score (max)		0.020		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: chr1-165175271;