Genetic Variant LMX1A:p.Thr295Ala (chr1-165205969-T-C) – ACMG Classification: Likely_benign (-2 pts)

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.81

Publications

0 publications found

Variant links:

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 links:

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

LMX1A-AS2 links:

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ACMG classification

Classification was made for transcript

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 link	c.883A>G	p.Thr295Ala	missense_variant	Exon 8 of 9	ENST00000342310.7	NP_796372.1	Q8TE12-1
LMX1A	NM_001174069.2 link	c.883A>G	p.Thr295Ala	missense_variant	Exon 8 of 9		NP_001167540.1	Q8TE12-1
LMX1A	XM_011509538.4 link	c.643A>G	p.Thr215Ala	missense_variant	Exon 6 of 7		XP_011507840.1
LMX1A-AS2	XR_922234.2 link	n.366+199T>C		intron_variant	Intron 2 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LMX1A	ENST00000342310.7 link	c.883A>G	p.Thr295Ala	missense_variant	Exon 8 of 9	2	NM_177398.4	ENSP00000340226.3	Q8TE12-1
LMX1A	ENST00000367893.4 link	c.883A>G	p.Thr295Ala	missense_variant	Exon 7 of 8	1		ENSP00000356868.4	Q8TE12-1
LMX1A	ENST00000489443.2 link	n.517A>G		non_coding_transcript_exon_variant	Exon 6 of 7	1
LMX1A	ENST00000294816.6 link	c.883A>G	p.Thr295Ala	missense_variant	Exon 8 of 9	2		ENSP00000294816.2	Q8TE12-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000201

AC:

AN:

249056

AF XY:

0.0000223

show subpopulations

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:

AN:

1460900

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

726738

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33414

American (AMR)

AF:

0.00

AC:

AN:

44578

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26066

East Asian (EAS)

AF:

0.00

AC:

AN:

39634

South Asian (SAS)

AF:

0.000163

AC:

AN:

86136

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111576

Other (OTH)

AF:

0.00

AC:

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000330

AC:

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

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

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

LIST_S2

Benign

0.59

.;.;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.090

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.20

N;N;N

PhyloP100

4.8

PrimateAI

Uncertain

0.49

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

GERP RS

4.3

Varity_R

0.073

gMVP

0.21

Mutation Taster

=89/11

polymorphism

(source)

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

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1-165205969-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over