dbSNP rs879255556: KLHL7:p.Cys421Ser (chr7-23167919-T-A) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3PP5

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

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:3

Conservation

PhyloP100: 7.67

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 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 PERCHING syndrome, retinitis pigmentosa 42, cold-induced sweating syndrome, retinitis pigmentosa.

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. Variant chr7-23167919-T-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL7	NM_001031710.3 link	c.1261T>A	p.Cys421Ser	missense_variant	Exon 9 of 11	ENST00000339077.10	NP_001026880.2	Q8IXQ5-1A8K364
KLHL7	NM_018846.5 link	c.1117T>A	p.Cys373Ser	missense_variant	Exon 9 of 11		NP_061334.4	Q8IXQ5-5
KLHL7	NR_033328.2 link	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 link	c.1261T>A	p.Cys421Ser	missense_variant	Exon 9 of 11	1	NM_001031710.3	ENSP00000343273.4		Q8IXQ5-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

PERCHING syndrome

Pathogenic:2

Jan 10, 2022

Istanbul Faculty of Medicine, Istanbul University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 09, 2020

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

BayesDel_noAF

Uncertain

0.10

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.17

T;.

Eigen

Benign

0.033

Eigen_PC

Benign

0.21

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.85

T;T

M_CAP

Benign

0.064

MetaRNN

Pathogenic

0.81

D;D

MetaSVM

Benign

-0.60

MutationAssessor

Benign

-0.77

N;.

PrimateAI

Pathogenic

0.86

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

GERP RS

5.7

Varity_R

0.59

gMVP

0.85

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over