1-165205901-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_177398.4(LMX1A):c.951C>T(p.Thr317=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00209 in 1,614,056 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (17 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (31 hom.)
• Consequence: LMX1A NM_177398.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.672

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:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 1-165205901-G-A is Benign according to our data. Variant chr1-165205901-G-A is described in ClinVar as [Benign]. Clinvar id is 777953.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.672 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0106 (1616/152236) while in subpopulation AFR AF= 0.037 (1538/41530). AF 95% confidence interval is 0.0355. There are 17 homozygotes in gnomad4. There are 740 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1614 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMX1A	NM_177398.4	c.951C>T	p.Thr317=	synonymous_variant	8/9	ENST00000342310.7
LMX1A-AS2	XR_922234.2	n.366+131G>A		intron_variant, non_coding_transcript_variant
LMX1A	NM_001174069.2	c.951C>T	p.Thr317=	synonymous_variant	8/9
LMX1A	XM_011509538.4	c.711C>T	p.Thr237=	synonymous_variant	6/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMX1A	ENST00000342310.7	c.951C>T	p.Thr317=	synonymous_variant	8/9	2	NM_177398.4	P1
LMX1A	ENST00000367893.4	c.951C>T	p.Thr317=	synonymous_variant	7/8	1		P1
LMX1A	ENST00000489443.2	n.585C>T		non_coding_transcript_exon_variant	6/7	1
LMX1A	ENST00000294816.6	c.951C>T	p.Thr317=	synonymous_variant	8/9	2		P1

Frequencies

GnomAD3 genomes AF: 0.0106 AC: 1614 AN: 152118 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.0371

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.00275 AC: 692 AN: 251398 Hom.: 12 AF XY: 0.00185 AC XY: 252 AN XY: 135856

Gnomad AFR exome AF: 0.0375

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00120 AC: 1751 AN: 1461820 Hom.: 31 Cov.: 31 AF XY: 0.00100 AC XY: 728 AN XY: 727208

Gnomad4 AFR exome AF: 0.0390

Gnomad4 AMR exome AF: 0.00195

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000123

Gnomad4 OTH exome AF: 0.00313

GnomAD4 genome AF: 0.0106 AC: 1616 AN: 152236 Hom.: 17 Cov.: 32 AF XY: 0.00994 AC XY: 740 AN XY: 74432

Gnomad4 AFR AF: 0.0370

Gnomad4 AMR AF: 0.00372

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00663

Alfa AF: 0.00340 Hom.: 4

Bravo AF: 0.0123

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

LMX1A-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 20, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Apr 30, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
Cadd	Benign	6.5
Dann	Benign	0.76

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

Publications

LitVar

Other links and lift over

dbSNP: rs35130714; hg19: chr1-165175138;