3-3845704-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_020873.7(LRRN1):ā€‹c.1063A>Gā€‹(p.Lys355Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,910 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

LRRN1
NM_020873.7 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.87
Variant links:
Genes affected
LRRN1 (HGNC:20980): (leucine rich repeat neuronal 1) Predicted to act upstream of or within positive regulation of synapse assembly. Predicted to be integral component of membrane. Predicted to be active in extracellular matrix and extracellular space. [provided by Alliance of Genome Resources, Apr 2022]
SUMF1 (HGNC:20376): (sulfatase modifying factor 1) This gene encodes an enzyme that catalyzes the hydrolysis of sulfate esters by oxidizing a cysteine residue in the substrate sulfatase to an active site 3-oxoalanine residue, which is also known as C-alpha-formylglycine. Mutations in this gene cause multiple sulfatase deficiency, a lysosomal storage disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.079749376).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
LRRN1NM_020873.7 linkuse as main transcriptc.1063A>G p.Lys355Glu missense_variant 2/2 ENST00000319331.4 NP_065924.3
LRRN1NM_001324188.2 linkuse as main transcriptc.1063A>G p.Lys355Glu missense_variant 3/3 NP_001311117.1
LRRN1NM_001324189.2 linkuse as main transcriptc.1063A>G p.Lys355Glu missense_variant 3/3 NP_001311118.1
LRRN1XM_047448644.1 linkuse as main transcriptc.1063A>G p.Lys355Glu missense_variant 2/2 XP_047304600.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
LRRN1ENST00000319331.4 linkuse as main transcriptc.1063A>G p.Lys355Glu missense_variant 2/21 NM_020873.7 ENSP00000314901 P1
SUMF1ENST00000448413.5 linkuse as main transcriptc.1192-18195T>C intron_variant, NMD_transcript_variant 2 ENSP00000404384

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152048
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
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
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461862
Hom.:
0
Cov.:
74
AF XY:
0.00000138
AC XY:
1
AN XY:
727232
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
152048
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74258
show subpopulations
Gnomad4 AFR
AF:
0.00
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
Alfa
AF:
0.0000282
Hom.:
0
Bravo
AF:
0.00000378

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 GeneticsMay 08, 2024The c.1063A>G (p.K355E) alteration is located in exon 2 (coding exon 1) of the LRRN1 gene. This alteration results from a A to G substitution at nucleotide position 1063, causing the lysine (K) at amino acid position 355 to be replaced by a glutamic acid (E). 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
0.086
BayesDel_addAF
Benign
-0.12
T
BayesDel_noAF
Benign
-0.41
CADD
Benign
15
DANN
Benign
0.92
DEOGEN2
Benign
0.017
T
Eigen
Benign
-0.45
Eigen_PC
Benign
-0.22
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Benign
0.84
T
M_CAP
Benign
0.0083
T
MetaRNN
Benign
0.080
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.31
N
MutationTaster
Benign
1.0
D;N
PrimateAI
Uncertain
0.63
T
PROVEAN
Benign
0.52
N
REVEL
Benign
0.065
Sift
Benign
0.95
T
Sift4G
Benign
1.0
T
Polyphen
0.0040
B
Vest4
0.34
MutPred
0.29
Loss of ubiquitination at K355 (P = 0.0134);
MVP
0.27
MPC
0.26
ClinPred
0.12
T
GERP RS
4.4
Varity_R
0.086
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: rs1023810279; hg19: chr3-3887388; API