1-165206005-T-A

Position:

chr1-165206005-T-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_177398.4(LMX1A):c.847A>T(p.Met283Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000505 in 1,584,306 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

LMX1A
NM_177398.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.22

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:):

LMX1A-AS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09088209).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
LMX1A	NM_177398.4 linkuse as main transcript	c.847A>T	p.Met283Leu	missense_variant	8/9	ENST00000342310.7	NP_796372.1
LMX1A-AS2	XR_922234.2 linkuse as main transcript	n.366+235T>A		intron_variant, non_coding_transcript_variant
LMX1A	NM_001174069.2 linkuse as main transcript	c.847A>T	p.Met283Leu	missense_variant	8/9		NP_001167540.1
LMX1A	XM_011509538.4 linkuse as main transcript	c.607A>T	p.Met203Leu	missense_variant	6/7		XP_011507840.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMX1A	ENST00000342310.7 linkuse as main transcript	c.847A>T	p.Met283Leu	missense_variant	8/9	2	NM_177398.4	ENSP00000340226	P1	Q8TE12-1
LMX1A	ENST00000367893.4 linkuse as main transcript	c.847A>T	p.Met283Leu	missense_variant	7/8	1		ENSP00000356868	P1	Q8TE12-1
LMX1A	ENST00000489443.2 linkuse as main transcript	n.481A>T		non_coding_transcript_exon_variant	6/7	1
LMX1A	ENST00000294816.6 linkuse as main transcript	c.847A>T	p.Met283Leu	missense_variant	8/9	2		ENSP00000294816	P1	Q8TE12-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

151870

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000968

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000446

AC:

AN:

224330

Hom.:

AF XY:

0.00

AC XY:

AN XY:

120908

show subpopulations

Gnomad AFR exome

AF:

0.0000654

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.00000279

AC:

AN:

1432436

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

710228

show subpopulations

Gnomad4 AFR exome

AF:

0.0000624

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:

0.0000339

GnomAD4 genome

AF:

0.0000263

AC:

AN:

151870

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74190

show subpopulations

Gnomad4 AFR

AF:

0.0000968

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 21, 2024

The c.847A>T (p.M283L) alteration is located in exon 8 (coding exon 7) of the LMX1A gene. This alteration results from a A to T substitution at nucleotide position 847, causing the methionine (M) at amino acid position 283 to be replaced by a leucine (L). 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

0.071

BayesDel_addAF

Benign

-0.058

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.31

T;T;T

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.18

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.55

.;.;T

M_CAP

Benign

0.0099

MetaRNN

Benign

0.091

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;N;N

MutationTaster

Benign

0.89

D;D;D

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.92

N;N;N

REVEL

Benign

0.20

Sift

Benign

0.24

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.18

MutPred

0.21

Loss of glycosylation at S280 (P = 0.1443);Loss of glycosylation at S280 (P = 0.1443);Loss of glycosylation at S280 (P = 0.1443);

MVP

0.43

MPC

0.23

ClinPred

0.31

GERP RS

4.3

Varity_R

0.13

gMVP

0.19

Splicing

Name

Calibrated prediction

Score

Prediction

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over