chr13-69719490-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_020866.3(KLHL1):​c.1894C>G​(p.Pro632Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000409 in 1,613,294 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P632S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

KLHL1
NM_020866.3 missense

Scores

3
12
4

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.14

Publications

0 publications found
Variant links:
Genes affected
KLHL1 (HGNC:6352): (kelch like family member 1) The KLHL1 protein belongs to a family of actin-organizing proteins related to Drosophila Kelch (Nemes et al., 2000 [PubMed 10888605]).[supplied by OMIM, Feb 2010]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.75

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KLHL1NM_020866.3 linkc.1894C>G p.Pro632Ala missense_variant Exon 9 of 11 ENST00000377844.9 NP_065917.1 Q9NR64Q8TBJ7
KLHL1NM_001286725.2 linkc.1711C>G p.Pro571Ala missense_variant Exon 8 of 10 NP_001273654.1 Q9NR64F5H1J3Q8TBJ7B7Z3I8
KLHL1XM_017020678.3 linkc.1375C>G p.Pro459Ala missense_variant Exon 9 of 11 XP_016876167.1
KLHL1XM_017020679.2 linkc.1225C>G p.Pro409Ala missense_variant Exon 9 of 11 XP_016876168.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KLHL1ENST00000377844.9 linkc.1894C>G p.Pro632Ala missense_variant Exon 9 of 11 1 NM_020866.3 ENSP00000367075.4 Q9NR64
KLHL1ENST00000545028.2 linkc.1711C>G p.Pro571Ala missense_variant Exon 8 of 10 2 ENSP00000439602.2 F5H1J3

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
151888
Hom.:
0
Cov.:
31
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
GnomAD2 exomes
AF:
0.0000199
AC:
5
AN:
250992
AF XY:
0.0000221
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 FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000441
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000445
AC:
65
AN:
1461406
Hom.:
0
Cov.:
31
AF XY:
0.0000509
AC XY:
37
AN XY:
727000
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33454
American (AMR)
AF:
0.00
AC:
0
AN:
44652
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26116
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39690
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86248
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53402
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000576
AC:
64
AN:
1111700
Other (OTH)
AF:
0.0000166
AC:
1
AN:
60376
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.484
Heterozygous variant carriers
0
4
7
11
14
18
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
4
8
12
16
20
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
151888
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
74140
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41364
American (AMR)
AF:
0.00
AC:
0
AN:
15182
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5168
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4814
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10588
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
67992
Other (OTH)
AF:
0.00
AC:
0
AN:
2082
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.625
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0000675
Hom.:
0
Bravo
AF:
0.0000151
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.00000824
AC:
1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.095
BayesDel_addAF
Uncertain
0.095
D
BayesDel_noAF
Uncertain
0.010
CADD
Pathogenic
27
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.69
D;.
Eigen
Uncertain
0.54
Eigen_PC
Uncertain
0.62
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.87
D;D
M_CAP
Benign
0.062
D
MetaRNN
Pathogenic
0.75
D;D
MetaSVM
Uncertain
0.088
D
MutationAssessor
Benign
1.4
L;.
PhyloP100
8.1
PrimateAI
Uncertain
0.72
T
PROVEAN
Pathogenic
-5.9
D;.
REVEL
Uncertain
0.57
Sift
Uncertain
0.027
D;.
Sift4G
Uncertain
0.016
D;D
Polyphen
0.70
P;.
Vest4
0.71
MVP
0.90
MPC
0.21
ClinPred
0.65
D
GERP RS
5.8
Varity_R
0.30
gMVP
0.34
Mutation Taster
=50/50

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

Other links and lift over

dbSNP: rs141275075; hg19: chr13-70293622; API