rs17147682

Variant names:

• chr7-23117963-A-G
• rs17147682
• ENST00000521082.5:n.*127A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000521082.5(KLHL7):​n.*127A>G variant causes a splice region, non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00862 in 1,614,014 control chromosomes in the GnomAD database, including 598 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.022 (140 hom., cov: 32)
  • Exomes 𝑓: 0.0072 (458 hom.)
• Consequence: KLHL7 ENST00000521082.5 splice_region, non_coding_transcript_exon
• Scores: Splicing: ADA: 0.0003823
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.43
• Publications: 6 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012262166).
• BP6: Variant 7-23117963-A-G is Benign according to our data. Variant chr7-23117963-A-G is described in ClinVar as Benign. ClinVar VariationId is 802301.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.146 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL7	NM_001031710.3	c.121-5814A>G		intron_variant	Intron 1 of 10	ENST00000339077.10	NP_001026880.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHL7	ENST00000339077.10	c.121-5814A>G		intron_variant	Intron 1 of 10	1	NM_001031710.3	ENSP00000343273.4

Frequencies

GnomAD3 genomes AF: 0.0217 AC: 3295 AN: 152192 Hom.: 138 Cov.: 32

Gnomad AFR AF: 0.0503

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0111

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.154

Gnomad SAS AF: 0.0211

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.000794

Gnomad OTH AF: 0.0220

GnomAD2 exomes AF: 0.0195 AC: 4895 AN: 251292 AF XY: 0.0179

Gnomad AFR exome AF: 0.0506

Gnomad AMR exome AF: 0.00651

Gnomad ASJ exome AF: 0.00218

Gnomad EAS exome AF: 0.164

Gnomad FIN exome AF: 0.00265

Gnomad NFE exome AF: 0.00161

Gnomad OTH exome AF: 0.00848

GnomAD4 exome AF: 0.00725 AC: 10596 AN: 1461704 Hom.: 458 Cov.: 31 AF XY: 0.00727 AC XY: 5288 AN XY: 727158

African (AFR) AF: 0.0511 AC: 1709 AN: 33474

American (AMR) AF: 0.00631 AC: 282 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00168 AC: 44 AN: 26132

East Asian (EAS) AF: 0.130 AC: 5172 AN: 39686

South Asian (SAS) AF: 0.0169 AC: 1454 AN: 86250

European-Finnish (FIN) AF: 0.00340 AC: 181 AN: 53278

Middle Eastern (MID) AF: 0.00919 AC: 53 AN: 5768

European-Non Finnish (NFE) AF: 0.000705 AC: 784 AN: 1112004

Other (OTH) AF: 0.0152 AC: 917 AN: 60388

GnomAD4 genome AF: 0.0217 AC: 3311 AN: 152310 Hom.: 140 Cov.: 32 AF XY: 0.0220 AC XY: 1639 AN XY: 74488

African (AFR) AF: 0.0505 AC: 2100 AN: 41558

American (AMR) AF: 0.0111 AC: 170 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.155 AC: 802 AN: 5176

South Asian (SAS) AF: 0.0217 AC: 105 AN: 4830

European-Finnish (FIN) AF: 0.00198 AC: 21 AN: 10626

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.000779 AC: 53 AN: 68022

Other (OTH) AF: 0.0213 AC: 45 AN: 2112

Alfa AF: 0.0153 Hom.: 63

Bravo AF: 0.0238

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.0454 AC: 200

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.0198 AC: 2408

Asia WGS AF: 0.0690 AC: 239 AN: 3478

EpiCase AF: 0.00115

EpiControl AF: 0.00154

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

PERCHING syndrome Benign:1

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	14
DANN	Benign	0.81
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.29	T
MetaRNN	Benign	0.0012	T
MetaSVM	Benign	-1.1	T
PhyloP100		1.4
PROVEAN	Benign	1.3	N
REVEL	Benign	0.069
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.085
ClinPred		0.0018	T
GERP RS		3.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00038
dbscSNV1_RF	Benign	0.046
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: rs17147682; hg19: chr7-23157582; COSMIC: COSV59163373;