rs137853112

Positions:

• chr7-23140775-G-A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_001031710.3(KLHL7):​c.449G>A​(p.Ser150Asn) variant causes a missense change. 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KLHL7 NM_001031710.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.17

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]

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM1: In a domain BACK (size 102) in uniprot entity KLHL7_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_001031710.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KLHL7. . Gene score misZ 3.907 (greater than the threshold 3.09). Trascript score misZ 5.0301 (greater than threshold 3.09). GenCC has associacion of gene with PERCHING syndrome, retinitis pigmentosa 42, cold-induced sweating syndrome, retinitis pigmentosa.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945
• PP5: Variant 7-23140775-G-A is Pathogenic according to our data. Variant chr7-23140775-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL7	NM_001031710.3	c.449G>A	p.Ser150Asn	missense_variant	5/11	ENST00000339077.10	NP_001026880.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL7	ENST00000339077.10	c.449G>A	p.Ser150Asn	missense_variant	5/11	1	NM_001031710.3	ENSP00000343273	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 03, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; One published functional study was unable to demonstrate any obvious effects on KLHL7 function, and additional studies are needed to further investigate this variant (Kigoshi et al., 2011); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27392078, 22084217, 31429209, 30997404, 19520207, 21828050) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 22, 2023	This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 150 of the KLHL7 protein (p.Ser150Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant retinitis pigmentosa (PMID: 19520207, 22084217). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1008). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on KLHL7 function (PMID: 21828050). For these reasons, this variant has been classified as Pathogenic. -

Retinitis pigmentosa 42 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2009

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Uncertain	0.029	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.038	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	1.0	L;.
MutationTaster	Benign	1.0	A;A;A;A;A;A
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	0.13	N;N
REVEL	Uncertain	0.30
Sift	Uncertain	0.0080	D;D
Sift4G	Benign	0.32	T;T
Polyphen		0.80	P;.
Vest4		0.90
MutPred		0.88		Loss of helix (P = 0.1299);.;
MVP		0.82
MPC		1.9
ClinPred		0.85	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.57
gMVP		0.74

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

Other links and lift over

dbSNP: rs137853112; hg19: chr7-23180394;