Genetic Variant LMX1A:c.747+62G>T (chr1-165210637-C-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.747+62G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.031 in 1,265,156 control chromosomes in the GnomAD database, including 3,036 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.091 ( 1678 hom., cov: 33)

Exomes 𝑓: 0.023 ( 1358 hom. )

Consequence

LMX1A
NM_177398.4 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0600

Publications

1 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=-0.8).

BP6

Variant 1-165210637-C-A is Benign according to our data. Variant chr1-165210637-C-A is described in ClinVar as [Benign]. Clinvar id is 1244331.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.27 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMX1A	NM_177398.4 link	c.747+62G>T		intron_variant	Intron 6 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.747+62G>T		intron_variant	Intron 6 of 8	2	NM_177398.4	ENSP00000340226.3		Q8TE12-1

Frequencies

GnomAD3 genomes

AF:

0.0905

AC:

13762

AN:

152034

Hom.:

1674

Cov.:

show subpopulations

Gnomad AFR

AF:

0.275

Gnomad AMI

AF:

0.0242

Gnomad AMR

AF:

0.0541

Gnomad ASJ

AF:

0.0352

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.00560

Gnomad FIN

AF:

0.0139

Gnomad MID

AF:

0.117

Gnomad NFE

AF:

0.0155

Gnomad OTH

AF:

0.0819

GnomAD4 exome

AF:

0.0228

AC:

25404

AN:

1113004

Hom.:

1358

Cov.:

AF XY:

0.0215

AC XY:

12208

AN XY:

567988

show subpopulations

African (AFR)

AF:

0.287

AC:

7671

AN:

26684

American (AMR)

AF:

0.0367

AC:

1571

AN:

42804

Ashkenazi Jewish (ASJ)

AF:

0.0402

AC:

939

AN:

23332

East Asian (EAS)

AF:

0.0000265

AC:

AN:

37678

South Asian (SAS)

AF:

0.00587

AC:

449

AN:

76504

European-Finnish (FIN)

AF:

0.0127

AC:

670

AN:

52720

Middle Eastern (MID)

AF:

0.109

AC:

560

AN:

5126

European-Non Finnish (NFE)

AF:

0.0145

AC:

11624

AN:

799554

Other (OTH)

AF:

0.0395

AC:

1919

AN:

48602

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1084

2169

3253

4338

5422

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0906

AC:

13780

AN:

152152

Hom.:

1678

Cov.:

AF XY:

0.0877

AC XY:

6521

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.275

AC:

11385

AN:

41464

American (AMR)

AF:

0.0539

AC:

825

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0352

AC:

122

AN:

3470

East Asian (EAS)

AF:

0.000385

AC:

AN:

5190

South Asian (SAS)

AF:

0.00477

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0139

AC:

147

AN:

10602

Middle Eastern (MID)

AF:

0.116

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0154

AC:

1049

AN:

68000

Other (OTH)

AF:

0.0810

AC:

171

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

531

1061

1592

2122

2653

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0392

Hom.:

740

Bravo

AF:

0.104

Asia WGS

AF:

0.0220

AC:

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 14, 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

-0.80

CADD

Benign

2.3

(source)

DANN

Benign

0.47

PhyloP100

0.060

Mutation Taster

=100/0

polymorphism (auto)

(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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chr1-165210637-C-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