3-3845589-G-C

Variant summary

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

The NM_020873.7(LRRN1):ā€‹c.948G>Cā€‹(p.Lys316Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,140 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 32)

Consequence

LRRN1
NM_020873.7 missense

Scores

3
9
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.10
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]

Genome browser will be placed here

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 Protein UniProt
LRRN1NM_020873.7 linkuse as main transcriptc.948G>C p.Lys316Asn missense_variant 2/2 ENST00000319331.4 NP_065924.3
LRRN1NM_001324188.2 linkuse as main transcriptc.948G>C p.Lys316Asn missense_variant 3/3 NP_001311117.1
LRRN1NM_001324189.2 linkuse as main transcriptc.948G>C p.Lys316Asn missense_variant 3/3 NP_001311118.1
LRRN1XM_047448644.1 linkuse as main transcriptc.948G>C p.Lys316Asn 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.948G>C p.Lys316Asn missense_variant 2/21 NM_020873.7 ENSP00000314901 P1
SUMF1ENST00000448413.5 linkuse as main transcriptc.1192-18080C>G intron_variant, NMD_transcript_variant 2 ENSP00000404384

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152140
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251096
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135692
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:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000881
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Cov.:
74
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152140
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74312
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:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000282
Hom.:
0
Bravo
AF:
0.00000756
ExAC
AF:
0.00000824
AC:
1

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 GeneticsApr 20, 2023The c.948G>C (p.K316N) alteration is located in exon 2 (coding exon 1) of the LRRN1 gene. This alteration results from a G to C substitution at nucleotide position 948, causing the lysine (K) at amino acid position 316 to be replaced by an asparagine (N). 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
1.0
BayesDel_addAF
Benign
-0.042
T
BayesDel_noAF
Benign
-0.30
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.21
T
Eigen
Uncertain
0.41
Eigen_PC
Uncertain
0.35
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Pathogenic
0.99
D
M_CAP
Benign
0.042
D
MetaRNN
Uncertain
0.65
D
MetaSVM
Benign
-0.67
T
MutationAssessor
Uncertain
2.4
M
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.82
D
PROVEAN
Uncertain
-3.5
D
REVEL
Benign
0.27
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.0020
D
Polyphen
1.0
D
Vest4
0.71
MutPred
0.45
Loss of ubiquitination at K316 (P = 0.0103);
MVP
0.52
MPC
0.80
ClinPred
0.98
D
GERP RS
2.5
Varity_R
0.69
gMVP
0.61

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: rs772303652; hg19: chr3-3887273; API