8-91124578-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001129890.2(LRRC69):ā€‹c.269T>Cā€‹(p.Leu90Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000011 in 1,541,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000020 ( 0 hom., cov: 32)
Exomes š‘“: 0.000010 ( 0 hom. )

Consequence

LRRC69
NM_001129890.2 missense

Scores

7
7
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.48
Variant links:
Genes affected
LRRC69 (HGNC:34303): (leucine rich repeat containing 69) Predicted to be involved in signal transduction. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.967

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
LRRC69NM_001129890.2 linkuse as main transcriptc.269T>C p.Leu90Ser missense_variant 2/8 ENST00000448384.3 NP_001123362.1
LRRC69NM_001354470.2 linkuse as main transcriptc.183+21734T>C intron_variant NP_001341399.1
LRRC69NR_148895.2 linkuse as main transcriptn.556-2510T>C intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
LRRC69ENST00000448384.3 linkuse as main transcriptc.269T>C p.Leu90Ser missense_variant 2/85 NM_001129890.2 ENSP00000400803 P1Q6ZNQ3-1
LRRC69ENST00000343709.7 linkuse as main transcriptc.183+21734T>C intron_variant 2 ENSP00000343221 Q6ZNQ3-2
LRRC69ENST00000522144.1 linkuse as main transcriptn.210T>C non_coding_transcript_exon_variant 2/22
LRRC69ENST00000520099.5 linkuse as main transcriptc.*303-2510T>C intron_variant, NMD_transcript_variant 2 ENSP00000428537

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
151946
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
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
GnomAD4 exome
AF:
0.0000101
AC:
14
AN:
1389928
Hom.:
0
Cov.:
29
AF XY:
0.00000875
AC XY:
6
AN XY:
685516
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:
0.0000121
Gnomad4 OTH exome
AF:
0.0000173
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
151946
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74206
show subpopulations
Gnomad4 AFR
AF:
0.0000241
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:
0.0000283
Hom.:
0
Bravo
AF:
0.0000264

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 GeneticsMar 27, 2023The c.269T>C (p.L90S) alteration is located in exon 2 (coding exon 2) of the LRRC69 gene. This alteration results from a T to C substitution at nucleotide position 269, causing the leucine (L) at amino acid position 90 to be replaced by a serine (S). 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
0.91
BayesDel_addAF
Pathogenic
0.26
D
BayesDel_noAF
Uncertain
0.13
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Benign
0.24
T
Eigen
Pathogenic
0.82
Eigen_PC
Pathogenic
0.70
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Benign
0.59
T
M_CAP
Benign
0.076
D
MetaRNN
Pathogenic
0.97
D
MetaSVM
Uncertain
-0.11
T
MutationAssessor
Pathogenic
3.9
H
MutationTaster
Benign
0.98
D;D
PrimateAI
Benign
0.46
T
PROVEAN
Pathogenic
-5.5
D
REVEL
Uncertain
0.54
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.0020
D
Polyphen
1.0
D
Vest4
0.85
MutPred
0.86
Gain of disorder (P = 0.0102);
MVP
0.28
ClinPred
1.0
D
GERP RS
5.5
Varity_R
0.86

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: rs1186926028; hg19: chr8-92136806; API