chr6-63280128-C-T

Variant summary

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

The NM_016571.3(LGSN):​c.1423G>A​(p.Ala475Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A475P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

LGSN
NM_016571.3 missense

Scores

1
11
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.62
Variant links:
Genes affected
LGSN (HGNC:21016): (lengsin, lens protein with glutamine synthetase domain) This gene encodes a protein with similarity to the GS I members of the glutamine synthetase superfamily. The encoded protein is referred to as a pseudo-glutamine synthetase because it has no glutamine synthesis activity and may function as a chaperone protein. This protein is localized to the lens and may be associated with cataract disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2009]

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ACMG classification

Classification made for transcript

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 UniProt
LGSNNM_016571.3 linkuse as main transcriptc.1423G>A p.Ala475Thr missense_variant 4/4 ENST00000370657.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
LGSNENST00000370657.9 linkuse as main transcriptc.1423G>A p.Ala475Thr missense_variant 4/41 NM_016571.3 P1Q5TDP6-1
LGSNENST00000370658.9 linkuse as main transcriptc.*375G>A 3_prime_UTR_variant 5/51 Q5TDP6-2
LGSNENST00000622415.1 linkuse as main transcriptc.*1148G>A 3_prime_UTR_variant 5/52 Q5TDP6-3
LGSNENST00000485906.6 linkuse as main transcriptc.530-701G>A intron_variant 3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251426
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135890
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS 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:
0.00000479
AC:
7
AN:
1461884
Hom.:
0
Cov.:
32
AF XY:
0.00000275
AC XY:
2
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000126
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Asia WGS
AF:
0.00144
AC:
5
AN:
3478

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 submitterclinical testingAmbry GeneticsJun 28, 2022The c.1423G>A (p.A475T) alteration is located in exon 4 (coding exon 4) of the LGSN gene. This alteration results from a G to A substitution at nucleotide position 1423, causing the alanine (A) at amino acid position 475 to be replaced by a threonine (T). 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
0.11
BayesDel_addAF
Benign
-0.035
T
BayesDel_noAF
Benign
-0.12
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.18
T
Eigen
Uncertain
0.50
Eigen_PC
Uncertain
0.48
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Benign
0.77
T
M_CAP
Uncertain
0.11
D
MetaRNN
Uncertain
0.55
D
MetaSVM
Uncertain
0.30
D
MutationAssessor
Uncertain
2.9
M
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.52
T
PROVEAN
Uncertain
-3.0
D
REVEL
Uncertain
0.48
Sift
Uncertain
0.0040
D
Sift4G
Benign
0.12
T
Polyphen
0.88
P
Vest4
0.38
MutPred
0.68
Gain of phosphorylation at A475 (P = 0.0964);
MVP
0.84
MPC
0.040
ClinPred
0.94
D
GERP RS
6.0
Varity_R
0.65
gMVP
0.46

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

LitVar

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

Other links and lift over

dbSNP: rs916438780; hg19: chr6-63990033; API