rs1394437

Variant names:

• chr1-165245068-A-G
• rs1394437
• NM_177398.4:c.496+4340T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_177398.4(LMX1A):​c.496+4340T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.662 in 151,892 control chromosomes in the GnomAD database, including 34,339 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.66 (34339 hom., cov: 30)
• Consequence: LMX1A NM_177398.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.454
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss 7

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
• Mobius syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hearing loss, autosomal recessive

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.819 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMX1A	NM_177398.4	c.496+4340T>C		intron_variant	Intron 4 of 8	ENST00000342310.7	NP_796372.1
LMX1A	NM_001174069.2	c.496+4340T>C		intron_variant	Intron 4 of 8		NP_001167540.1
LMX1A	XM_011509538.4	c.256+4340T>C		intron_variant	Intron 2 of 6		XP_011507840.1
LMX1A	XM_011509540.3	c.496+4340T>C		intron_variant	Intron 4 of 7		XP_011507842.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LMX1A	ENST00000342310.7	c.496+4340T>C		intron_variant	Intron 4 of 8	2	NM_177398.4	ENSP00000340226.3
LMX1A	ENST00000367893.4	c.496+4340T>C		intron_variant	Intron 3 of 7	1		ENSP00000356868.4
LMX1A	ENST00000294816.6	c.496+4340T>C		intron_variant	Intron 4 of 8	2		ENSP00000294816.2

Frequencies

GnomAD3 genomes AF: 0.661 AC: 100381 AN: 151774 Hom.: 34289 Cov.: 30

Gnomad AFR AF: 0.826

Gnomad AMI AF: 0.515

Gnomad AMR AF: 0.585

Gnomad ASJ AF: 0.694

Gnomad EAS AF: 0.361

Gnomad SAS AF: 0.520

Gnomad FIN AF: 0.575

Gnomad MID AF: 0.658

Gnomad NFE AF: 0.625

Gnomad OTH AF: 0.669

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.662 AC: 100478 AN: 151892 Hom.: 34339 Cov.: 30 AF XY: 0.651 AC XY: 48330 AN XY: 74206

African (AFR) AF: 0.826 AC: 34210 AN: 41424

American (AMR) AF: 0.584 AC: 8911 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.694 AC: 2410 AN: 3472

East Asian (EAS) AF: 0.360 AC: 1857 AN: 5154

South Asian (SAS) AF: 0.519 AC: 2483 AN: 4782

European-Finnish (FIN) AF: 0.575 AC: 6059 AN: 10534

Middle Eastern (MID) AF: 0.660 AC: 194 AN: 294

European-Non Finnish (NFE) AF: 0.625 AC: 42465 AN: 67960

Other (OTH) AF: 0.673 AC: 1421 AN: 2112

Alfa AF: 0.650 Hom.: 5267

Bravo AF: 0.674

Asia WGS AF: 0.508 AC: 1763 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.1
DANN	Benign	0.54
PhyloP100		0.45
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1394437; hg19: chr1-165214305;