Genetic Variant NM_019117.5:c.728-145C>T (chrX-87617787-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_019117.5(KLHL4):c.728-145C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.4 in 441,702 control chromosomes in the GnomAD database, including 25,621 homozygotes. There are 54,232 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.38 ( 5973 hom., 11872 hem., cov: 23)

Exomes 𝑓: 0.41 ( 19648 hom. 42360 hem. )

Consequence

KLHL4
NM_019117.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.01

Publications

0 publications found

Variant links:

Genes affected

KLHL4 (HGNC:6355): (kelch like family member 4) This gene encodes a member of the kelch family of proteins, which are characterized by kelch repeat motifs and a POZ/BTB protein-binding domain. It is thought that kelch repeats are actin binding domains. However, the specific function of this protein has not been determined. Alternative splicing of this gene results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

KLHL4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.96).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.449 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
KLHL4	NM_019117.5 link	c.728-145C>T	intron_variant	Intron 3 of 10	ENST00000373119.9	NP_061990.2	Q9C0H6-1A5PKX1
KLHL4	NM_057162.3 link	c.728-145C>T	intron_variant	Intron 3 of 10		NP_476503.1	Q9C0H6-2
KLHL4	XR_938403.3 link	n.820-145C>T	intron_variant	Intron 3 of 11

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
KLHL4	ENST00000373119.9 link	c.728-145C>T	intron_variant	Intron 3 of 10	1	NM_019117.5	ENSP00000362211.4	Q9C0H6-1
KLHL4	ENST00000373114.4 link	c.728-145C>T	intron_variant	Intron 3 of 10	1		ENSP00000362206.4	Q9C0H6-2
KLHL4	ENST00000652270.1 link	n.728-145C>T	intron_variant	Intron 3 of 11			ENSP00000498718.1	Q9C0H6-1

Frequencies

GnomAD3 genomes

AF:

0.376

AC:

41444

AN:

110365

Hom.:

5980

Cov.:

show subpopulations

Gnomad AFR

AF:

0.268

Gnomad AMI

AF:

0.578

Gnomad AMR

AF:

0.331

Gnomad ASJ

AF:

0.485

Gnomad EAS

AF:

0.226

Gnomad SAS

AF:

0.288

Gnomad FIN

AF:

0.353

Gnomad MID

AF:

0.482

Gnomad NFE

AF:

0.454

Gnomad OTH

AF:

0.389

GnomAD4 exome

AF:

0.408

AC:

135254

AN:

331292

Hom.:

19648

AF XY:

0.411

AC XY:

42360

AN XY:

103178

show subpopulations

African (AFR)

AF:

0.273

AC:

2675

AN:

9789

American (AMR)

AF:

0.278

AC:

3820

AN:

13734

Ashkenazi Jewish (ASJ)

AF:

0.491

AC:

4681

AN:

9537

East Asian (EAS)

AF:

0.252

AC:

5847

AN:

23237

South Asian (SAS)

AF:

0.299

AC:

5931

AN:

19843

European-Finnish (FIN)

AF:

0.363

AC:

10933

AN:

30135

Middle Eastern (MID)

AF:

0.473

AC:

642

AN:

1357

European-Non Finnish (NFE)

AF:

0.455

AC:

92894

AN:

204215

Other (OTH)

AF:

0.403

AC:

7831

AN:

19445

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

2696

5392

8088

10784

13480

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

732

1464

2196

2928

3660

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.375

AC:

41435

AN:

110410

Hom.:

5973

Cov.:

AF XY:

0.363

AC XY:

11872

AN XY:

32716

show subpopulations

African (AFR)

AF:

0.267

AC:

8133

AN:

30405

American (AMR)

AF:

0.331

AC:

3413

AN:

10311

Ashkenazi Jewish (ASJ)

AF:

0.485

AC:

1275

AN:

2628

East Asian (EAS)

AF:

0.226

AC:

787

AN:

3482

South Asian (SAS)

AF:

0.290

AC:

768

AN:

2651

European-Finnish (FIN)

AF:

0.353

AC:

2033

AN:

5765

Middle Eastern (MID)

AF:

0.480

AC:

AN:

204

European-Non Finnish (NFE)

AF:

0.454

AC:

23965

AN:

52802

Other (OTH)

AF:

0.386

AC:

577

AN:

1494

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

944

1888

2833

3777

4721

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

404

808

1212

1616

2020

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.407

Hom.:

2764

Bravo

AF:

0.366

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

0.14

(source)

DANN

Benign

0.44

PhyloP100

-1.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over