Genetic Variant LMX1A:c.670-76A>T (chr1-165210852-T-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_177398.4(LMX1A):c.670-76A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.732 in 1,018,780 control chromosomes in the GnomAD database, including 279,651 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.77 ( 46753 hom., cov: 32)

Exomes 𝑓: 0.72 ( 232898 hom. )

Consequence

LMX1A
NM_177398.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.922

Publications

16 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 1-165210852-T-A is Benign according to our data. Variant chr1-165210852-T-A is described in ClinVar as [Benign]. Clinvar id is 1225418.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.925 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMX1A	NM_177398.4 link	c.670-76A>T		intron_variant	Intron 5 of 8	ENST00000342310.7	NP_796372.1	Q8TE12-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LMX1A	ENST00000342310.7 link	c.670-76A>T		intron_variant	Intron 5 of 8	2	NM_177398.4	ENSP00000340226.3		Q8TE12-1

Frequencies

GnomAD3 genomes

AF:

0.772

AC:

117336

AN:

152020

Hom.:

46708

Cov.:

show subpopulations

Gnomad AFR

AF:

0.933

Gnomad AMI

AF:

0.916

Gnomad AMR

AF:

0.640

Gnomad ASJ

AF:

0.665

Gnomad EAS

AF:

0.356

Gnomad SAS

AF:

0.587

Gnomad FIN

AF:

0.718

Gnomad MID

AF:

0.782

Gnomad NFE

AF:

0.760

Gnomad OTH

AF:

0.762

GnomAD4 exome

AF:

0.724

AC:

627878

AN:

866642

Hom.:

232898

Cov.:

AF XY:

0.721

AC XY:

320556

AN XY:

444598

show subpopulations

African (AFR)

AF:

0.940

AC:

19697

AN:

20954

American (AMR)

AF:

0.497

AC:

16698

AN:

33564

Ashkenazi Jewish (ASJ)

AF:

0.684

AC:

13660

AN:

19976

East Asian (EAS)

AF:

0.362

AC:

12394

AN:

34244

South Asian (SAS)

AF:

0.598

AC:

35587

AN:

59480

European-Finnish (FIN)

AF:

0.731

AC:

35447

AN:

48492

Middle Eastern (MID)

AF:

0.776

AC:

3448

AN:

4442

European-Non Finnish (NFE)

AF:

0.763

AC:

461880

AN:

605638

Other (OTH)

AF:

0.729

AC:

29067

AN:

39852

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

7794

15589

23383

31178

38972

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.772

AC:

117431

AN:

152138

Hom.:

46753

Cov.:

AF XY:

0.761

AC XY:

56607

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.932

AC:

38723

AN:

41526

American (AMR)

AF:

0.640

AC:

9780

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.665

AC:

2308

AN:

3470

East Asian (EAS)

AF:

0.355

AC:

1835

AN:

5172

South Asian (SAS)

AF:

0.588

AC:

2822

AN:

4802

European-Finnish (FIN)

AF:

0.718

AC:

7588

AN:

10568

Middle Eastern (MID)

AF:

0.793

AC:

233

AN:

294

European-Non Finnish (NFE)

AF:

0.760

AC:

51695

AN:

67994

Other (OTH)

AF:

0.763

AC:

1612

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1271

2542

3813

5084

6355

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.730

Hom.:

20034

Bravo

AF:

0.772

Asia WGS

AF:

0.510

AC:

1773

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 12, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.13

(source)

DANN

Benign

0.51

PhyloP100

-0.92

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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1-165210852-T-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over