1-165205969-T-G

Position:

chr1-165205969-T-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_177398.4(LMX1A):c.883A>C(p.Thr295Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000104 in 1,613,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.00052 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000060 ( 0 hom. )

Consequence

LMX1A
NM_177398.4 missense

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 4.81

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:40343): (LMX1A antisense RNA 2)

LMX1A-AS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0067626834).

BP6

Variant 1-165205969-T-G is Benign according to our data. Variant chr1-165205969-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 3048621.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000519 (79/152180) while in subpopulation AFR AF= 0.00185 (77/41510). AF 95% confidence interval is 0.00152. There are 0 homozygotes in gnomad4. There are 40 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 79 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMX1A	NM_177398.4 linkuse as main transcript	c.883A>C	p.Thr295Pro	missense_variant	8/9	ENST00000342310.7	NP_796372.1	Q8TE12-1
LMX1A	NM_001174069.2 linkuse as main transcript	c.883A>C	p.Thr295Pro	missense_variant	8/9		NP_001167540.1	Q8TE12-1
LMX1A	XM_011509538.4 linkuse as main transcript	c.643A>C	p.Thr215Pro	missense_variant	6/7		XP_011507840.1
LMX1A-AS2	XR_922234.2 linkuse as main transcript	n.366+199T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
LMX1A	ENST00000342310.7 linkuse as main transcript	c.883A>C	p.Thr295Pro	missense_variant	8/9	2	NM_177398.4	ENSP00000340226.3	Q8TE12-1
LMX1A	ENST00000367893.4 linkuse as main transcript	c.883A>C	p.Thr295Pro	missense_variant	7/8	1		ENSP00000356868.4	Q8TE12-1
LMX1A	ENST00000489443.2 linkuse as main transcript	n.517A>C		non_coding_transcript_exon_variant	6/7	1
LMX1A	ENST00000294816.6 linkuse as main transcript	c.883A>C	p.Thr295Pro	missense_variant	8/9	2		ENSP00000294816.2	Q8TE12-1

Frequencies

GnomAD3 genomes

AF:

0.000520

AC:

AN:

152062

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00186

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000177

AC:

AN:

249056

Hom.:

AF XY:

0.000119

AC XY:

AN XY:

134572

show subpopulations

Gnomad AFR exome

AF:

0.00260

Gnomad AMR exome

AF:

0.0000292

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.0000602

AC:

AN:

1460900

Hom.:

Cov.:

AF XY:

0.0000468

AC XY:

AN XY:

726738

show subpopulations

Gnomad4 AFR exome

AF:

0.00245

Gnomad4 AMR exome

AF:

0.0000673

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000519

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.000538

AC XY:

AN XY:

74414

show subpopulations

Gnomad4 AFR

AF:

0.00185

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0255

Hom.:

2352

Bravo

AF:

0.000774

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000239

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

LMX1A-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 21, 2022

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.052

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Benign

0.68

DEOGEN2

Benign

0.26

T;T;T

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.24

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.58

.;.;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.0068

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.2

N;N;N

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.34

N;N;N

REVEL

Benign

0.22

Sift

Benign

0.80

T;T;T

Sift4G

Benign

0.39

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.19

MVP

0.33

MPC

0.32

ClinPred

0.017

GERP RS

4.3

Varity_R

0.12

gMVP

0.14

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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