Variant 1-165205937-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_177398.4(LMX1A):c.915T>G(p.Ser305Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

LMX1A
NM_177398.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.769

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.42162195).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
LMX1A	NM_177398.4 linkuse as main transcript	c.915T>G	p.Ser305Arg	missense_variant	8/9	ENST00000342310.7	NP_796372.1
LMX1A-AS2	XR_922234.2 linkuse as main transcript	n.366+167A>C		intron_variant, non_coding_transcript_variant
LMX1A	NM_001174069.2 linkuse as main transcript	c.915T>G	p.Ser305Arg	missense_variant	8/9		NP_001167540.1
LMX1A	XM_011509538.4 linkuse as main transcript	c.675T>G	p.Ser225Arg	missense_variant	6/7		XP_011507840.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMX1A	ENST00000342310.7 linkuse as main transcript	c.915T>G	p.Ser305Arg	missense_variant	8/9	2	NM_177398.4	ENSP00000340226	P1	Q8TE12-1
LMX1A	ENST00000367893.4 linkuse as main transcript	c.915T>G	p.Ser305Arg	missense_variant	7/8	1		ENSP00000356868	P1	Q8TE12-1
LMX1A	ENST00000489443.2 linkuse as main transcript	n.549T>G		non_coding_transcript_exon_variant	6/7	1
LMX1A	ENST00000294816.6 linkuse as main transcript	c.915T>G	p.Ser305Arg	missense_variant	8/9	2		ENSP00000294816	P1	Q8TE12-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

6.84e-7

AC:

AN:

1461718

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727166

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 7

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

Jun 22, 2023

The observed missense variant c.915T>G(p.Ser305Arg) in LMX1A gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Ser305Arg variant is absent in gnomAD Exomes. The amino acid Ser at position 305 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. Computational evidence (Polyphen-probably damaging, SIFT-damaging and Mutation Taster-polymorphism) predicts conflicting evidence on protein structure and function for this variant. For these reasons, this variant has been classified as Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.62

BayesDel_addAF

Benign

0.0071

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.54

D;D;D

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.21

LIST_S2

Uncertain

0.86

.;.;D

M_CAP

Benign

0.056

MetaRNN

Benign

0.42

T;T;T

MetaSVM

Benign

-0.30

MutationAssessor

Benign

1.5

L;L;L

MutationTaster

Benign

0.93

N;N;N

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-2.1

N;N;N

REVEL

Uncertain

0.46

Sift

Benign

0.17

T;T;T

Sift4G

Benign

0.14

T;T;T

Polyphen

0.95

P;P;P

Vest4

0.56

MutPred

0.33

Gain of catalytic residue at S305 (P = 0.0345);Gain of catalytic residue at S305 (P = 0.0345);Gain of catalytic residue at S305 (P = 0.0345);

MVP

0.43

MPC

0.41

ClinPred

0.84

GERP RS

-8.2

Varity_R

0.21

gMVP

0.28

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over