chr1-165205914-C-A

Variant names:

• chr1-165205914-C-A
• NM_177398.4:c.938G>T

Variant summary

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

The NM_177398.4(LMX1A):​c.938G>T​(p.Arg313Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,818 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R313Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LMX1A NM_177398.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.85

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMX1A	NM_177398.4	c.938G>T	p.Arg313Leu	missense_variant	Exon 8 of 9	ENST00000342310.7	NP_796372.1
LMX1A	NM_001174069.2	c.938G>T	p.Arg313Leu	missense_variant	Exon 8 of 9		NP_001167540.1
LMX1A	XM_011509538.4	c.698G>T	p.Arg233Leu	missense_variant	Exon 6 of 7		XP_011507840.1
LMX1A-AS2	XR_922234.2	n.366+144C>A		intron_variant	Intron 2 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LMX1A	ENST00000342310.7	c.938G>T	p.Arg313Leu	missense_variant	Exon 8 of 9	2	NM_177398.4	ENSP00000340226.3
LMX1A	ENST00000367893.4	c.938G>T	p.Arg313Leu	missense_variant	Exon 7 of 8	1		ENSP00000356868.4
LMX1A	ENST00000489443.2	n.572G>T		non_coding_transcript_exon_variant	Exon 6 of 7	1
LMX1A	ENST00000294816.6	c.938G>T	p.Arg313Leu	missense_variant	Exon 8 of 9	2		ENSP00000294816.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461818 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727208

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D;D;D
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	.;.;D
M_CAP	Benign	0.072	D
MetaRNN	Uncertain	0.65	D;D;D
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.2	M;M;M
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.4	N;N;N
REVEL	Uncertain	0.37
Sift	Uncertain	0.024	D;D;D
Sift4G	Benign	0.35	T;T;T
Polyphen		0.88	P;P;P
Vest4		0.71
MutPred		0.32		Loss of catalytic residue at R313 (P = 0.0481);Loss of catalytic residue at R313 (P = 0.0481);Loss of catalytic residue at R313 (P = 0.0481);
MVP		0.62
MPC		0.43
ClinPred		0.96	D
GERP RS		5.4
Varity_R		0.21
gMVP		0.36

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: chr1-165175151;