NM_177398.4:c.1050T>C

Variant names:

• chr1-165203979-A-G
• rs1354509
• NM_177398.4:c.1050T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_177398.4(LMX1A):​c.1050T>C​(p.Asp350Asp) variant causes a synonymous change. The variant allele was found at a frequency of 1 in 1,614,162 control chromosomes in the GnomAD database, including 806,768 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 1.0 (75984 hom., cov: 31)
  • Exomes 𝑓: 1.0 (730784 hom.)
• Consequence: LMX1A NM_177398.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.70
• Publications: 14 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-AS2 (HGNC:40343): (LMX1A antisense RNA 2)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 1-165203979-A-G is Benign according to our data. Variant chr1-165203979-A-G is described in ClinVar as [Benign]. Clinvar id is 1294826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMX1A	NM_177398.4	c.1050T>C	p.Asp350Asp	synonymous_variant	Exon 9 of 9	ENST00000342310.7	NP_796372.1
LMX1A	NM_001174069.2	c.1050T>C	p.Asp350Asp	synonymous_variant	Exon 9 of 9		NP_001167540.1
LMX1A	XM_011509538.4	c.810T>C	p.Asp270Asp	synonymous_variant	Exon 7 of 7		XP_011507840.1
LMX1A-AS2	XR_922234.2	n.-68A>G		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LMX1A	ENST00000342310.7	c.1050T>C	p.Asp350Asp	synonymous_variant	Exon 9 of 9	2	NM_177398.4	ENSP00000340226.3
LMX1A	ENST00000367893.4	c.1050T>C	p.Asp350Asp	synonymous_variant	Exon 8 of 8	1		ENSP00000356868.4
LMX1A	ENST00000489443.2	n.684T>C		non_coding_transcript_exon_variant	Exon 7 of 7	1
LMX1A	ENST00000294816.6	c.1050T>C	p.Asp350Asp	synonymous_variant	Exon 9 of 9	2		ENSP00000294816.2

Frequencies

GnomAD3 genomes AF: 0.999 AC: 152010 AN: 152170 Hom.: 75925 Cov.: 31

Gnomad AFR AF: 0.996

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.999

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 1.00

GnomAD2 exomes AF: 1.00 AC: 251399 AN: 251476 AF XY: 1.00

Gnomad AFR exome AF: 0.996

Gnomad AMR exome AF: 1.00

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 1.00

GnomAD4 exome AF: 1.00 AC: 1461720 AN: 1461874 Hom.: 730784 Cov.: 49 AF XY: 1.00 AC XY: 727177 AN XY: 727236

African (AFR) AF: 0.996 AC: 33359 AN: 33480

American (AMR) AF: 1.00 AC: 44713 AN: 44724

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26136 AN: 26136

East Asian (EAS) AF: 1.00 AC: 39700 AN: 39700

South Asian (SAS) AF: 1.00 AC: 86253 AN: 86256

European-Finnish (FIN) AF: 1.00 AC: 53420 AN: 53420

Middle Eastern (MID) AF: 1.00 AC: 5767 AN: 5768

European-Non Finnish (NFE) AF: 1.00 AC: 1111996 AN: 1111996

Other (OTH) AF: 1.00 AC: 60376 AN: 60394

GnomAD4 genome AF: 0.999 AC: 152128 AN: 152288 Hom.: 75984 Cov.: 31 AF XY: 0.999 AC XY: 74365 AN XY: 74448

African (AFR) AF: 0.996 AC: 41403 AN: 41554

American (AMR) AF: 0.999 AC: 15289 AN: 15298

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5162 AN: 5162

South Asian (SAS) AF: 1.00 AC: 4822 AN: 4822

European-Finnish (FIN) AF: 1.00 AC: 10624 AN: 10624

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68038 AN: 68038

Other (OTH) AF: 1.00 AC: 2114 AN: 2114

Alfa AF: 0.999 Hom.: 22086

Bravo AF: 0.999

Asia WGS AF: 0.999 AC: 3476 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Autosomal dominant nonsyndromic hearing loss 7 Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	11
DANN	Benign	0.57
PhyloP100		3.7
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: rs1354509; hg19: chr1-165173216; COSMIC: COSV108110179;