chr1-165214730-G-C

Variant names:

• chr1-165214730-G-C
• rs6668493
• NM_177398.4:c.497-917C>G

Variant summary

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

The NM_177398.4(LMX1A):​c.497-917C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 152,270 control chromosomes in the GnomAD database, including 904 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 0.11 (904 hom., cov: 33)
• Consequence: LMX1A NM_177398.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.339
• Publications: 2 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: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.156 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.497-917C>G		intron	N/A	NP_796372.1	Q8TE12-1
	LMX1A	NM_001174069.2		c.497-917C>G		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.497-917C>G		intron	N/A	ENSP00000340226.3	Q8TE12-1
	LMX1A	ENST00000367893.4	TSL:1	c.497-917C>G		intron	N/A	ENSP00000356868.4	Q8TE12-1
	LMX1A	ENST00000294816.6	TSL:2	c.497-917C>G		intron	N/A	ENSP00000294816.2	Q8TE12-1

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16261 AN: 152150 Hom.: 898 Cov.: 33

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.0980

Gnomad AMR AF: 0.0894

Gnomad ASJ AF: 0.0994

Gnomad EAS AF: 0.141

Gnomad SAS AF: 0.165

Gnomad FIN AF: 0.0596

Gnomad MID AF: 0.109

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.112

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

GnomAD4 genome AF: 0.107 AC: 16286 AN: 152270 Hom.: 904 Cov.: 33 AF XY: 0.104 AC XY: 7774 AN XY: 74450

African (AFR) AF: 0.104 AC: 4310 AN: 41560

American (AMR) AF: 0.0890 AC: 1361 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0994 AC: 345 AN: 3470

East Asian (EAS) AF: 0.141 AC: 731 AN: 5190

South Asian (SAS) AF: 0.165 AC: 796 AN: 4824

European-Finnish (FIN) AF: 0.0596 AC: 632 AN: 10608

Middle Eastern (MID) AF: 0.127 AC: 37 AN: 292

European-Non Finnish (NFE) AF: 0.114 AC: 7733 AN: 68020

Other (OTH) AF: 0.119 AC: 252 AN: 2114

Alfa AF: 0.101 Hom.: 111

Bravo AF: 0.106

Asia WGS AF: 0.141 AC: 494 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.59
DANN	Benign	0.44
PhyloP100		-0.34
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: rs6668493; hg19: chr1-165183967;