Genetic Variant NM_017644.3:c.-61-147T>C (chr3-183650149-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_017644.3(KLHL24):c.-61-147T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.293 in 479,834 control chromosomes in the GnomAD database, including 22,938 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.33 ( 9392 hom., cov: 32)

Exomes 𝑓: 0.27 ( 13546 hom. )

Consequence

KLHL24
NM_017644.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0520

Variant links:

Genes affected

KLHL24 (HGNC:25947): (kelch like family member 24) The protein encoded by this gene is a ubiquitin ligase substrate receptor and is regulated by autoubiquitination. Variations in the translation initiation codon of this gene have been found, which result in an N-terminally truncated but more stable protein due to loss of the autoubiquitination function. The more stable mutant protein causes an increased ubiquitin and degradation of keratin 14, which leads to skin fragility and the potentially life-threatening disease epidermolysis bullosa. The encoded protein is also involved in the regulation of kainate receptors. [provided by RefSeq, Mar 2017]

KLHL24 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BP6

Variant 3-183650149-T-C is Benign according to our data. Variant chr3-183650149-T-C is described in ClinVar as [Benign]. Clinvar id is 1222273.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.483 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL24	NM_017644.3 link	c.-61-147T>C		intron_variant	Intron 2 of 7	ENST00000242810.11	NP_060114.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHL24	ENST00000242810.11 link	c.-61-147T>C		intron_variant	Intron 2 of 7	1	NM_017644.3	ENSP00000242810.6		Q6TFL4-1

Frequencies

GnomAD3 genomes

AF:

0.335

AC:

50861

AN:

151962

Hom.:

9372

Cov.:

show subpopulations

Gnomad AFR

AF:

0.488

Gnomad AMI

AF:

0.365

Gnomad AMR

AF:

0.318

Gnomad ASJ

AF:

0.279

Gnomad EAS

AF:

0.476

Gnomad SAS

AF:

0.189

Gnomad FIN

AF:

0.228

Gnomad MID

AF:

0.383

Gnomad NFE

AF:

0.263

Gnomad OTH

AF:

0.345

GnomAD4 exome

AF:

0.274

AC:

89744

AN:

327754

Hom.:

13546

AF XY:

0.269

AC XY:

45681

AN XY:

169650

show subpopulations

Gnomad4 AFR exome

AF:

0.494

Gnomad4 AMR exome

AF:

0.291

Gnomad4 ASJ exome

AF:

0.275

Gnomad4 EAS exome

AF:

0.461

Gnomad4 SAS exome

AF:

0.186

Gnomad4 FIN exome

AF:

0.218

Gnomad4 NFE exome

AF:

0.254

Gnomad4 OTH exome

AF:

0.288

GnomAD4 genome

AF:

0.335

AC:

50926

AN:

152080

Hom.:

9392

Cov.:

AF XY:

0.329

AC XY:

24474

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.489

Gnomad4 AMR

AF:

0.317

Gnomad4 ASJ

AF:

0.279

Gnomad4 EAS

AF:

0.476

Gnomad4 SAS

AF:

0.189

Gnomad4 FIN

AF:

0.228

Gnomad4 NFE

AF:

0.263

Gnomad4 OTH

AF:

0.349

Alfa

AF:

0.129

Hom.:

192

Bravo

AF:

0.356

Asia WGS

AF:

0.326

AC:

1134

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 12, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

2.2

DANN

Benign

0.71

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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