Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1PM2PM5PP2PP3_StrongPP5

The NM_001031710.3(KLHL7):c.433A>G(p.Asn145Asp) 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N145Y) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Failed GnomAD Quality Control

Consequence

KLHL7
NM_001031710.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:1

Conservation

PhyloP100: 8.87

Publications

2 publications found

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]

KLHL7 Gene-Disease associations (from GenCC):

PERCHING syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Illumina
retinitis pigmentosa 42
Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
cold-induced sweating syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

KLHL7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001031710.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-23125163-A-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1285582.Status of the report is criteria_provided_single_submitter, 1 stars.

PP2

Missense variant in the KLHL7 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 12 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 3.907 (above the threshold of 3.09). Trascript score misZ: 5.0301 (above the threshold of 3.09). GenCC associations: The gene is linked to retinitis pigmentosa 42, PERCHING syndrome, retinitis pigmentosa, cold-induced sweating syndrome.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.948

PP5

Variant 7-23125163-A-G is Pathogenic according to our data. Variant chr7-23125163-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 438051.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001031710.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KLHL7	NM_001031710.3	MANE Select	c.433A>G	p.Asn145Asp	missense	Exon 4 of 11	NP_001026880.2
KLHL7	NM_018846.5		c.289A>G	p.Asn97Asp	missense	Exon 4 of 11	NP_061334.4
KLHL7	NM_001172428.2		c.433A>G	p.Asn145Asp	missense	Exon 4 of 5	NP_001165899.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KLHL7	ENST00000339077.10	TSL:1 MANE Select	c.433A>G	p.Asn145Asp	missense	Exon 4 of 11	ENSP00000343273.4
KLHL7	ENST00000409689.5	TSL:1	c.289A>G	p.Asn97Asp	missense	Exon 4 of 11	ENSP00000386263.1
KLHL7	ENST00000322275.9	TSL:1	c.433A>G	p.Asn145Asp	missense	Exon 4 of 5	ENSP00000323270.5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152228

Hom.:

Cov.:

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

Cov.:

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000657

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74368

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41464

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68044

Other (OTH)

AF:

0.00

AC:

AN:

2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Retinal dystrophy (2)

Retinitis pigmentosa (1)

Retinitis pigmentosa 42 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.020

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.95

MetaSVM

Uncertain

0.59

MutationAssessor

Pathogenic

3.2

PhyloP100

8.9

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-4.5

REVEL

Pathogenic

0.83

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.016

Polyphen

1.0

Vest4

0.93

MutPred

0.84

Loss of catalytic residue at N145 (P = 0.0757)

MVP

0.95

MPC

2.7

ClinPred

1.0

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.96

gMVP

0.93

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs1182983579

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over