rs879255556

Variant names:

• chr7-23167919-T-A
• rs879255556
• NM_001031710.3:c.1261T>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP2 PP3 PP5

The NM_001031710.3(KLHL7):​c.1261T>A​(p.Cys421Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KLHL7 NM_001031710.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:3
• Conservation: PhyloP100: 7.67
• Publications: 1 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, 0.815
• PP5: Variant 7-23167919-T-A is Pathogenic according to our data. Variant chr7-23167919-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 226127.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL7	NM_001031710.3	c.1261T>A	p.Cys421Ser	missense_variant	Exon 9 of 11	ENST00000339077.10	NP_001026880.2
KLHL7	NM_018846.5	c.1117T>A	p.Cys373Ser	missense_variant	Exon 9 of 11		NP_061334.4
KLHL7	NR_033328.2	n.1634T>A		non_coding_transcript_exon_variant	Exon 10 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHL7	ENST00000339077.10	c.1261T>A	p.Cys421Ser	missense_variant	Exon 9 of 11	1	NM_001031710.3	ENSP00000343273.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461878 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: no assertion criteria provided

Submissions by phenotype

PERCHING syndrome Pathogenic:2

Jan 09, 2020

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 10, 2022

Istanbul Faculty of Medicine, Istanbul University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cold-induced sweating syndrome 1 Pathogenic:1

Jan 01, 2016

National Research Council, Institute of Genetics and Biomedical Research

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	23
DANN	Benign	0.93
DEOGEN2	Benign	0.17	T;.
Eigen	Benign	0.033
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	T;T
M_CAP	Benign	0.064	D
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	-0.77	N;.
PhyloP100		7.7
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	1.9	N;N
REVEL	Uncertain	0.52
Sift	Benign	0.12	T;T
Sift4G	Benign	0.44	T;T
Polyphen		0.99	D;.
Vest4		0.92
MutPred		0.67		Gain of disorder (P = 3e-04);.;
MVP		0.89
MPC		0.94
ClinPred		0.87	D
GERP RS		5.7
Varity_R		0.59
gMVP		0.85
Mutation Taster		=2/98	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: rs879255556; hg19: chr7-23207538;