rs15775

Variant names:

• chr7-23125082-C-A
• rs15775
• NM_001031710.3:c.352C>A

Your query was ambiguous. Multiple possible variants found:

• chr7-23125082-C-A
• chr7-23125082-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_001031710.3(KLHL7):​c.352C>A​(p.Leu118Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L118L) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KLHL7 NM_001031710.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.43
• Publications: 28 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, 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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, 0.864

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL7	NM_001031710.3	c.352C>A	p.Leu118Met	missense_variant	Exon 4 of 11	ENST00000339077.10	NP_001026880.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHL7	ENST00000339077.10	c.352C>A	p.Leu118Met	missense_variant	Exon 4 of 11	1	NM_001031710.3	ENSP00000343273.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T;.;.;.
Eigen	Benign	0.18
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.86	D;D;D;D
MetaSVM	Uncertain	0.24	D
MutationAssessor	Benign	1.9	L;L;.;.
PhyloP100		1.4
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.7	N;N;N;N
REVEL	Pathogenic	0.66
Sift	Benign	0.085	T;D;T;D
Sift4G	Benign	0.17	T;D;T;D
Polyphen		0.78	P;D;.;D
Vest4		0.64
MutPred		0.75		Gain of catalytic residue at V114 (P = 0.0301);Gain of catalytic residue at V114 (P = 0.0301);.;.;
MVP		0.78
MPC		1.9
ClinPred		0.93	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.72
Mutation Taster		=72/28	polymorphism

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: rs15775; hg19: chr7-23164701; COSMIC: COSV59163593; COSMIC: COSV59163593;