Variant rs1554289078 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_001031710.3(KLHL7):c.618+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

KLHL7
NM_001031710.3 splice_donor

Scores

Splicing: ADA: 1.000

Clinical Significance

Likely pathogenic criteria provided, single submitter P:4

Conservation

PhyloP100: 9.52

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 7-23140945-G-A is Pathogenic according to our data. Variant chr7-23140945-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 487514.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL7	NM_001031710.3 linkuse as main transcript	c.618+1G>A		splice_donor_variant		ENST00000339077.10	NP_001026880.2

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	Appris	UniProt
KLHL7	ENST00000339077.10 linkuse as main transcript	c.618+1G>A	splice_donor_variant	1	NM_001031710.3	ENSP00000343273	P1	Q8IXQ5-1
KLHL7	ENST00000409689.5 linkuse as main transcript	c.474+1G>A	splice_donor_variant	1		ENSP00000386263		Q8IXQ5-5
KLHL7	ENST00000521082.5 linkuse as main transcript	c.*626+1G>A	splice_donor_variant, NMD_transcript_variant	1		ENSP00000430351
KLHL7	ENST00000479288.5 linkuse as main transcript	n.565+1G>A	splice_donor_variant, non_coding_transcript_variant	4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461008

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726874

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Ulnar deviation of the wrist

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Nov 01, 2016

- -

PERCHING syndrome

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 09, 2020

- -

Distal arthrogryposis

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Jan 01, 2014

- -

Retinitis pigmentosa 42

Pathogenic:1

Likely pathogenic, no assertion criteria provided

provider interpretation

Solve-RD Consortium

Jun 01, 2022

Variant confirmed as disease-causing by referring clinical team -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

MutationTaster

Benign

1.0

D;D;D;D;D;D

GERP RS

5.3

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.82

Position offset: -19

DS_DL_spliceai

1.0

Position offset: -1

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