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7-23125163-A-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate

The NM_001031710.3(KLHL7):c.433A>T(p.Asn145Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N145D) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

KLHL7
NM_001031710.3 missense

Scores

14
4
1

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 8.87
Variant links:
Genes affected
KLHL7 (HGNC:15646): (kelch like family member 7) This gene encodes a BTB-Kelch-related protein. The encoded protein may be involved in protein degradation. Mutations in this gene have been associated with retinitis pigmentosa 42. [provided by RefSeq, Feb 2010]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1
?
    PM1 - Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001031710.3
PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PM5
?
    PM5 - Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before
Other missense variant is known to change same aminoacid residue: Variant chr7-23125163-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 438051.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1, Pathogenic=1}.
PP2
?
    PP2 - Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease
Missense variant where missense usually causes diseases, KLHL7
PP3
?
    PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
MetaRNN computational evidence supports a deleterious effect, 0.967
PP5
?
    PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 7-23125163-A-T is Pathogenic according to our data. Variant chr7-23125163-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1285582.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-23125163-A-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
KLHL7NM_001031710.3 linkuse as main transcriptc.433A>T p.Asn145Tyr missense_variant 4/11 ENST00000339077.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
KLHL7ENST00000339077.10 linkuse as main transcriptc.433A>T p.Asn145Tyr missense_variant 4/111 NM_001031710.3 P1Q8IXQ5-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Retinitis pigmentosa 42 Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterSep 21, 2020- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.46
D
BayesDel_noAF
Pathogenic
0.42
Cadd
Pathogenic
29
Dann
Uncertain
0.99
DEOGEN2
Uncertain
0.58
D;.;.;.
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.95
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.97
D;D;D;D
M_CAP
Pathogenic
0.44
D
MetaRNN
Pathogenic
0.97
D;D;D;D
MetaSVM
Pathogenic
0.85
D
MutationAssessor
Pathogenic
4.2
H;H;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
0.81
D
PROVEAN
Pathogenic
-7.2
D;D;D;D
REVEL
Pathogenic
0.94
Sift
Pathogenic
0.0
D;D;D;D
Sift4G
Uncertain
0.0080
D;D;D;D
Polyphen
1.0
D;D;.;D
Vest4
0.93
MutPred
0.86
Gain of helix (P = 0.132);Gain of helix (P = 0.132);.;.;
MVP
0.97
MPC
2.8
ClinPred
1.0
D
GERP RS
5.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.98
gMVP
0.95

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-23164782; API