chr7-23106078-C-T

Variant names:

• chr7-23106078-C-T
• NM_001031710.3:c.52C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001031710.3(KLHL7):​c.52C>T​(p.Leu18Phe) 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 benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L18P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KLHL7 NM_001031710.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.79
• Publications: 0 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: Uncertain_significance. The variant received 1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.11263949).

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.52C>T	p.Leu18Phe	missense	Exon 1 of 11	NP_001026880.2	Q8IXQ5-1
	KLHL7	NM_001172428.2		c.52C>T	p.Leu18Phe	missense	Exon 1 of 5	NP_001165899.1	Q8IXQ5-3
	KLHL7	NR_033328.2		n.294C>T		non_coding_transcript_exon	Exon 1 of 12

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL7	ENST00000339077.10	TSL:1 MANE Select	c.52C>T	p.Leu18Phe	missense	Exon 1 of 11	ENSP00000343273.4	Q8IXQ5-1
	KLHL7	ENST00000322275.9	TSL:1	c.52C>T	p.Leu18Phe	missense	Exon 1 of 5	ENSP00000323270.5	Q8IXQ5-3
	KLHL7	ENST00000521082.5	TSL:1	n.52C>T		non_coding_transcript_exon	Exon 1 of 12	ENSP00000430351.1	E5RFN1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.040	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.34	N
PhyloP100		2.8
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.083
Sift	Benign	0.11	T
Sift4G	Benign	0.43	T
Polyphen		0.0060	B
Vest4		0.17
MutPred		0.43		Gain of methylation at K17 (P = 0.0377)
MVP		0.81
MPC		0.40
ClinPred		0.73	D
GERP RS		4.1
PromoterAI		0.0098	Neutral
Varity_R		0.078
gMVP		0.53
Mutation Taster		=79/21	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

hg19: chr7-23145697;