1-165204008-C-G

Position:

chr1-165204008-C-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BS1_SupportingBS2

The NM_177398.4(LMX1A):c.1021G>C(p.Asp341His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,613,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

LMX1A
NM_177398.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.37

Variant links:

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 links:

LMX1A-AS2 (HGNC:):

LMX1A-AS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.39409363).

BS1

Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000287 (42/1461830) while in subpopulation SAS AF= 0.000255 (22/86240). AF 95% confidence interval is 0.000173. There are 0 homozygotes in gnomad4_exome. There are 31 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAdExome4 at 42 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
LMX1A	NM_177398.4 linkuse as main transcript	c.1021G>C	p.Asp341His	missense_variant	9/9	ENST00000342310.7	NP_796372.1
LMX1A	NM_001174069.2 linkuse as main transcript	c.1021G>C	p.Asp341His	missense_variant	9/9		NP_001167540.1
LMX1A	XM_011509538.4 linkuse as main transcript	c.781G>C	p.Asp261His	missense_variant	7/7		XP_011507840.1
LMX1A-AS2	XR_922234.2 linkuse as main transcript			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMX1A	ENST00000342310.7 linkuse as main transcript	c.1021G>C	p.Asp341His	missense_variant	9/9	2	NM_177398.4	ENSP00000340226	P1	Q8TE12-1
LMX1A	ENST00000367893.4 linkuse as main transcript	c.1021G>C	p.Asp341His	missense_variant	8/8	1		ENSP00000356868	P1	Q8TE12-1
LMX1A	ENST00000489443.2 linkuse as main transcript	n.655G>C		non_coding_transcript_exon_variant	7/7	1
LMX1A	ENST00000294816.6 linkuse as main transcript	c.1021G>C	p.Asp341His	missense_variant	9/9	2		ENSP00000294816	P1	Q8TE12-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000477

AC:

AN:

251434

Hom.:

AF XY:

0.0000662

AC XY:

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000287

AC:

AN:

1461830

Hom.:

Cov.:

AF XY:

0.0000426

AC XY:

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000255

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000153

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74300

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 02, 2023

The c.1021G>C (p.D341H) alteration is located in exon 9 (coding exon 8) of the LMX1A gene. This alteration results from a G to C substitution at nucleotide position 1021, causing the aspartic acid (D) at amino acid position 341 to be replaced by a histidine (H). 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

Pathogenic

0.57

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.74

D;D;D

Eigen

Uncertain

0.68

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.85

.;.;T

M_CAP

Benign

0.080

MetaRNN

Benign

0.39

T;T;T

MetaSVM

Uncertain

0.31

MutationAssessor

Uncertain

2.3

M;M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-2.3

N;N;N

REVEL

Uncertain

0.52

Sift

Benign

0.21

T;T;T

Sift4G

Uncertain

0.011

D;D;D

Polyphen

0.99

D;D;D

Vest4

0.27

MutPred

0.34

Loss of stability (P = 0.0213);Loss of stability (P = 0.0213);Loss of stability (P = 0.0213);

MVP

0.64

MPC

0.90

ClinPred

0.91

GERP RS

4.9

Varity_R

0.22

gMVP

0.61

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over