1-165205915-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PVS1_StrongPP5_ModerateBS2

The NM_177398.4(LMX1A):c.937C>T(p.Arg313*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,461,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

LMX1A
NM_177398.4 stop_gained

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 9.34

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.185 CDS is truncated, and there are 1 pathogenic variants in the truncated region.

PP5

Variant 1-165205915-G-A is Pathogenic according to our data. Variant chr1-165205915-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2503455.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMX1A	NM_177398.4 link	c.937C>T	p.Arg313*	stop_gained	Exon 8 of 9	ENST00000342310.7	NP_796372.1	Q8TE12-1
LMX1A	NM_001174069.2 link	c.937C>T	p.Arg313*	stop_gained	Exon 8 of 9		NP_001167540.1	Q8TE12-1
LMX1A	XM_011509538.4 link	c.697C>T	p.Arg233*	stop_gained	Exon 6 of 7		XP_011507840.1
LMX1A-AS2	XR_922234.2 link	n.366+145G>A		intron_variant	Intron 2 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LMX1A	ENST00000342310.7 link	c.937C>T	p.Arg313*	stop_gained	Exon 8 of 9	2	NM_177398.4	ENSP00000340226.3	Q8TE12-1
LMX1A	ENST00000367893.4 link	c.937C>T	p.Arg313*	stop_gained	Exon 7 of 8	1		ENSP00000356868.4	Q8TE12-1
LMX1A	ENST00000489443.2 link	n.571C>T		non_coding_transcript_exon_variant	Exon 6 of 7	1
LMX1A	ENST00000294816.6 link	c.937C>T	p.Arg313*	stop_gained	Exon 8 of 9	2		ENSP00000294816.2	Q8TE12-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251412

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135866

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1461844

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000936

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 7

Pathogenic:1

May 31, 2023

Department of Human Genetics, Hannover Medical School

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration leads to a premature stop signal, most likely resulting in degradation of the formed mRNA via nonsense-mediated mRNA decay (NMD) and/or expression of a truncated protein. The population database gnomAD reports an allele frequency of 0.002% for the variant (gnomAD; ALL). Literature data are currently not available. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.61

BayesDel_noAF

Pathogenic

0.66

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.99

FATHMM_MKL

Pathogenic

0.99

Vest4

0.91

GERP RS

5.4

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

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