1-165205880-G-T

Variant names:

• chr1-165205880-G-T
• rs771369531
• NM_177398.4:c.972C>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_177398.4(LMX1A):​c.972C>A​(p.Asp324Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,461,758 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: LMX1A NM_177398.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.43
• Publications: 0 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: Likely_benign. The variant received -1 ACMG points.

• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.000013 (19/1461758) while in subpopulation AMR AF = 0.000425 (19/44724). AF 95% confidence interval is 0.000277. There are 0 homozygotes in GnomAdExome4. There are 9 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMX1A	NM_177398.4	c.972C>A	p.Asp324Glu	missense_variant	Exon 8 of 9	ENST00000342310.7	NP_796372.1
LMX1A	NM_001174069.2	c.972C>A	p.Asp324Glu	missense_variant	Exon 8 of 9		NP_001167540.1
LMX1A	XM_011509538.4	c.732C>A	p.Asp244Glu	missense_variant	Exon 6 of 7		XP_011507840.1
LMX1A-AS2	XR_922234.2	n.366+110G>T		intron_variant	Intron 2 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LMX1A	ENST00000342310.7	c.972C>A	p.Asp324Glu	missense_variant	Exon 8 of 9	2	NM_177398.4	ENSP00000340226.3
LMX1A	ENST00000367893.4	c.972C>A	p.Asp324Glu	missense_variant	Exon 7 of 8	1		ENSP00000356868.4
LMX1A	ENST00000489443.2	n.606C>A		non_coding_transcript_exon_variant	Exon 6 of 7	1
LMX1A	ENST00000294816.6	c.972C>A	p.Asp324Glu	missense_variant	Exon 8 of 9	2		ENSP00000294816.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000756 AC: 19 AN: 251362 AF XY: 0.0000663

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461758 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 727170

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.000425 AC: 19 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111980

Other (OTH) AF: 0.00 AC: 0 AN: 60376

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000576 AC: 7

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jan 20, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	T;T;T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.82	.;.;T
M_CAP	Uncertain	0.087	D
MetaRNN	Uncertain	0.57	D;D;D
MetaSVM	Uncertain	0.0056	D
MutationAssessor	Benign	1.8	L;L;L
PhyloP100		2.4
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.5	N;N;N
REVEL	Uncertain	0.46
Sift	Benign	0.092	T;T;T
Sift4G	Benign	0.11	T;T;T
Polyphen		1.0	D;D;D
Vest4		0.77
MutPred		0.17		Gain of glycosylation at P322 (P = 0.0856);Gain of glycosylation at P322 (P = 0.0856);Gain of glycosylation at P322 (P = 0.0856);
MVP		0.78
MPC		0.47
ClinPred		0.31	T
GERP RS		4.4
Varity_R		0.14
gMVP		0.15
Mutation Taster		=69/31	polymorphism

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: rs771369531; hg19: chr1-165175117;