chr1-165205969-T-C

Variant names:

• chr1-165205969-T-C
• rs148227502
• NM_177398.4:c.883A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_177398.4(LMX1A):​c.883A>G​(p.Thr295Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000958 in 1,460,900 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 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. T295P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: LMX1A NM_177398.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.81
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.089592904).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMX1A	NM_177398.4	c.883A>G	p.Thr295Ala	missense_variant	Exon 8 of 9	ENST00000342310.7	NP_796372.1
LMX1A	NM_001174069.2	c.883A>G	p.Thr295Ala	missense_variant	Exon 8 of 9		NP_001167540.1
LMX1A	XM_011509538.4	c.643A>G	p.Thr215Ala	missense_variant	Exon 6 of 7		XP_011507840.1
LMX1A-AS2	XR_922234.2	n.366+199T>C		intron_variant	Intron 2 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LMX1A	ENST00000342310.7	c.883A>G	p.Thr295Ala	missense_variant	Exon 8 of 9	2	NM_177398.4	ENSP00000340226.3
LMX1A	ENST00000367893.4	c.883A>G	p.Thr295Ala	missense_variant	Exon 7 of 8	1		ENSP00000356868.4
LMX1A	ENST00000489443.2	n.517A>G		non_coding_transcript_exon_variant	Exon 6 of 7	1
LMX1A	ENST00000294816.6	c.883A>G	p.Thr295Ala	missense_variant	Exon 8 of 9	2		ENSP00000294816.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000201 AC: 5 AN: 249056 AF XY: 0.0000223

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1460900 Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11 AN XY: 726738

African (AFR) AF: 0.00 AC: 0 AN: 33414

American (AMR) AF: 0.00 AC: 0 AN: 44578

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26066

East Asian (EAS) AF: 0.00 AC: 0 AN: 39634

South Asian (SAS) AF: 0.000163 AC: 14 AN: 86136

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111576

Other (OTH) AF: 0.00 AC: 0 AN: 60348

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000330 AC: 4

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Benign	0.31	T;T;T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.59	.;.;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.090	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.20	N;N;N
PhyloP100		4.8
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.75	N;N;N
REVEL	Benign	0.18
Sift	Benign	0.35	T;T;T
Sift4G	Benign	0.78	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.36
MutPred		0.19		Loss of phosphorylation at T295 (P = 0.021);Loss of phosphorylation at T295 (P = 0.021);Loss of phosphorylation at T295 (P = 0.021);
MVP		0.45
MPC		0.24
ClinPred		0.076	T
GERP RS		4.3
Varity_R		0.073
gMVP		0.21
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs148227502; hg19: chr1-165175206;