chr1-165317042-A-G

Variant names:

• chr1-165317042-A-G
• rs2348250
• NM_177398.4:c.263+36034T>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.263+36034T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.873 in 152,208 control chromosomes in the GnomAD database, including 58,483 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 0.87 (58483 hom., cov: 32)
• Consequence: LMX1A NM_177398.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00
• 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

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal dominant nonsyndromic hearing loss 7

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.925 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_177398.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LMX1A	NM_177398.4	MANE Select	c.263+36034T>C		intron	N/A	NP_796372.1	Q8TE12-1
	LMX1A	NM_001174069.2		c.263+36034T>C		intron	N/A	NP_001167540.1	Q8TE12-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LMX1A	ENST00000342310.7	TSL:2 MANE Select	c.263+36034T>C		intron	N/A	ENSP00000340226.3	Q8TE12-1
	LMX1A	ENST00000367893.4	TSL:1	c.263+36034T>C		intron	N/A	ENSP00000356868.4	Q8TE12-1
	LMX1A	ENST00000294816.6	TSL:2	c.263+36034T>C		intron	N/A	ENSP00000294816.2	Q8TE12-1

Frequencies

GnomAD3 genomes AF: 0.873 AC: 132784 AN: 152090 Hom.: 58441 Cov.: 32

Gnomad AFR AF: 0.751

Gnomad AMI AF: 0.907

Gnomad AMR AF: 0.891

Gnomad ASJ AF: 0.904

Gnomad EAS AF: 0.944

Gnomad SAS AF: 0.842

Gnomad FIN AF: 0.917

Gnomad MID AF: 0.914

Gnomad NFE AF: 0.931

Gnomad OTH AF: 0.868

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

GnomAD4 genome AF: 0.873 AC: 132879 AN: 152208 Hom.: 58483 Cov.: 32 AF XY: 0.871 AC XY: 64837 AN XY: 74416

African (AFR) AF: 0.751 AC: 31151 AN: 41486

American (AMR) AF: 0.892 AC: 13643 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.904 AC: 3140 AN: 3472

East Asian (EAS) AF: 0.944 AC: 4894 AN: 5184

South Asian (SAS) AF: 0.843 AC: 4067 AN: 4822

European-Finnish (FIN) AF: 0.917 AC: 9718 AN: 10598

Middle Eastern (MID) AF: 0.918 AC: 268 AN: 292

European-Non Finnish (NFE) AF: 0.931 AC: 63335 AN: 68028

Other (OTH) AF: 0.868 AC: 1836 AN: 2114

Alfa AF: 0.886 Hom.: 10448

Bravo AF: 0.864

Asia WGS AF: 0.868 AC: 3020 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.1
DANN	Benign	0.82
PhyloP100		0.0
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: rs2348250; hg19: chr1-165286279;