rs137853113

Variant names:

• chr7-23140784-C-T
• rs137853113
• NM_001031710.3:c.458C>T

Variant summary

Our verdict is Pathogenic. The variant received 23 ACMG points: 23P and 0B. PS3 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001031710.3(KLHL7):​c.458C>T​(p.Ala153Val) 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001397681: Experimental studies have shown that this missense change affects KLHL7 function (PMID:21828050)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A153T) has been classified as 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:12
• Conservation: PhyloP100: 7.50
• Publications: 16 publications found

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, Illumina, Ambry Genetics
• 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

ACMG classification

Our verdict: Pathogenic. The variant received 23 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001397681: Experimental studies have shown that this missense change affects KLHL7 function (PMID: 21828050).; SCV006103543: "Published functional studies demonstrate a damaging dominant-negative effect (PMID: 21828050)"
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 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 chr7-23140783-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1010.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, cold-induced sweating syndrome, retinitis pigmentosa, PERCHING syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 7-23140784-C-T is Pathogenic according to our data. Variant chr7-23140784-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1009.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL7	NM_001031710.3	MANE Select	c.458C>T	p.Ala153Val	missense	Exon 5 of 11	NP_001026880.2	Q8IXQ5-1
	KLHL7	NM_018846.5		c.314C>T	p.Ala105Val	missense	Exon 5 of 11	NP_061334.4
	KLHL7	NR_033328.2		n.831C>T		non_coding_transcript_exon	Exon 6 of 12

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL7	ENST00000339077.10	TSL:1 MANE Select	c.458C>T	p.Ala153Val	missense	Exon 5 of 11	ENSP00000343273.4	Q8IXQ5-1
	KLHL7	ENST00000409689.5	TSL:1	c.314C>T	p.Ala105Val	missense	Exon 5 of 11	ENSP00000386263.1	Q8IXQ5-5
	KLHL7	ENST00000521082.5	TSL:1	n.*466C>T		non_coding_transcript_exon	Exon 6 of 12	ENSP00000430351.1	E5RFN1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	not provided (4)
4	-	-	Retinitis pigmentosa 42 (4)
3	-	-	Retinal dystrophy (3)
1	-	-	Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		7.5
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.076	T
Polyphen		0.99	D
Vest4		0.98
MutPred		0.94		Loss of helix (P = 0.1706)
MVP		0.93
MPC		2.5
ClinPred		0.99	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.89
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs137853113; hg19: chr7-23180403;