chr1-165229089-T-C

Variant names:

• chr1-165229089-T-C
• rs1807837
• NM_177398.4:c.497-15276A>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.497-15276A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.122 in 152,040 control chromosomes in the GnomAD database, including 1,230 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 0.12 (1230 hom., cov: 32)
• Consequence: LMX1A NM_177398.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.213
• 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 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=-0.79).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.147 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMX1A	NM_177398.4	c.497-15276A>G		intron_variant	Intron 4 of 8	ENST00000342310.7	NP_796372.1
LMX1A	NM_001174069.2	c.497-15276A>G		intron_variant	Intron 4 of 8		NP_001167540.1
LMX1A	XM_011509538.4	c.257-15276A>G		intron_variant	Intron 2 of 6		XP_011507840.1
LMX1A	XM_011509540.3	c.497-15276A>G		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.497-15276A>G		intron_variant	Intron 4 of 8	2	NM_177398.4	ENSP00000340226.3
LMX1A	ENST00000367893.4	c.497-15276A>G		intron_variant	Intron 3 of 7	1		ENSP00000356868.4
LMX1A	ENST00000294816.6	c.497-15276A>G		intron_variant	Intron 4 of 8	2		ENSP00000294816.2

Frequencies

GnomAD3 genomes AF: 0.122 AC: 18509 AN: 151922 Hom.: 1227 Cov.: 32

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.173

Gnomad AMR AF: 0.125

Gnomad ASJ AF: 0.136

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0222

Gnomad FIN AF: 0.100

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.149

Gnomad OTH AF: 0.130

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

GnomAD4 genome AF: 0.122 AC: 18523 AN: 152040 Hom.: 1230 Cov.: 32 AF XY: 0.116 AC XY: 8638 AN XY: 74336

African (AFR) AF: 0.106 AC: 4381 AN: 41452

American (AMR) AF: 0.124 AC: 1899 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 471 AN: 3466

East Asian (EAS) AF: 0.00155 AC: 8 AN: 5174

South Asian (SAS) AF: 0.0231 AC: 111 AN: 4808

European-Finnish (FIN) AF: 0.100 AC: 1060 AN: 10594

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.149 AC: 10139 AN: 67966

Other (OTH) AF: 0.128 AC: 271 AN: 2114

Alfa AF: 0.126 Hom.: 159

Bravo AF: 0.125

Asia WGS AF: 0.0190 AC: 65 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.3
DANN	Benign	0.88
PhyloP100		-0.21
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: rs1807837; hg19: chr1-165198326;