rs137853114

Variant names:

• chr7-23140783-G-A
• rs137853114
• NM_001031710.3:c.457G>A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_001031710.3(KLHL7):​c.457G>A​(p.Ala153Thr) 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A153V) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KLHL7 NM_001031710.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.52
• Publications: 4 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: Pathogenic. The variant received 13 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, 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 chr7-23140784-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.
• 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, 0.983
• PP5: Variant 7-23140783-G-A is Pathogenic according to our data. 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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL7	NM_001031710.3	MANE Select	c.457G>A	p.Ala153Thr	missense	Exon 5 of 11	NP_001026880.2
	KLHL7	NM_018846.5		c.313G>A	p.Ala105Thr	missense	Exon 5 of 11	NP_061334.4
	KLHL7	NR_033328.2		n.830G>A		non_coding_transcript_exon	Exon 6 of 12

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL7	ENST00000339077.10	TSL:1 MANE Select	c.457G>A	p.Ala153Thr	missense	Exon 5 of 11	ENSP00000343273.4
	KLHL7	ENST00000409689.5	TSL:1	c.313G>A	p.Ala105Thr	missense	Exon 5 of 11	ENSP00000386263.1
	KLHL7	ENST00000521082.5	TSL:1	n.*465G>A		non_coding_transcript_exon	Exon 6 of 12	ENSP00000430351.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000654 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Retinal dystrophy (1)
1	-	-	Retinitis pigmentosa 42 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		9.5
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.079	T
Polyphen		0.99	D
Vest4		0.98
MutPred		0.94		Loss of helix (P = 0.1706)
MVP		0.93
MPC		2.2
ClinPred		0.99	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.74
gMVP		0.83
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: rs137853114; hg19: chr7-23180402; COSMIC: COSV59161231; COSMIC: COSV59161231;