1-165205929-C-A

Position:

• chr1-165205929-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_177398.4(LMX1A):​c.923G>T​(p.Ser308Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LMX1A NM_177398.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.10

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMX1A	NM_177398.4	c.923G>T	p.Ser308Ile	missense_variant	8/9	ENST00000342310.7	NP_796372.1
LMX1A	NM_001174069.2	c.923G>T	p.Ser308Ile	missense_variant	8/9		NP_001167540.1
LMX1A	XM_011509538.4	c.683G>T	p.Ser228Ile	missense_variant	6/7		XP_011507840.1
LMX1A-AS2	XR_922234.2	n.366+159C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMX1A	ENST00000342310.7	c.923G>T	p.Ser308Ile	missense_variant	8/9	2	NM_177398.4	ENSP00000340226.3
LMX1A	ENST00000367893.4	c.923G>T	p.Ser308Ile	missense_variant	7/8	1		ENSP00000356868.4
LMX1A	ENST00000489443.2	n.557G>T		non_coding_transcript_exon_variant	6/7	1
LMX1A	ENST00000294816.6	c.923G>T	p.Ser308Ile	missense_variant	8/9	2		ENSP00000294816.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 02, 2024

The c.923G>T (p.S308I) alteration is located in exon 8 (coding exon 7) of the LMX1A gene. This alteration results from a G to T substitution at nucleotide position 923, causing the serine (S) at amino acid position 308 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.77	D;D;D
Eigen	Benign	0.12
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	.;.;D
M_CAP	Benign	0.075	D
MetaRNN	Uncertain	0.45	T;T;T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	2.0	M;M;M
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.9	D;D;D
REVEL	Uncertain	0.43
Sift	Uncertain	0.023	D;D;D
Sift4G	Benign	0.16	T;T;T
Polyphen		0.86	P;P;P
Vest4		0.47
MutPred		0.32		Loss of disorder (P = 0.005);Loss of disorder (P = 0.005);Loss of disorder (P = 0.005);
MVP		0.61
MPC		0.47
ClinPred		0.97	D
GERP RS		1.9
Varity_R		0.16
gMVP		0.38

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-165175166;