rs113845886

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_014780.5(CUL7):c.1027C>T(p.Pro343Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00229 in 1,614,180 control chromosomes in the GnomAD database, including 81 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P343P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.013 ( 44 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 37 hom. )

Consequence

CUL7
NM_014780.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 3.48

Publications

2 publications found

Variant links:

Genes affected

CUL7 (HGNC:21024): (cullin 7) The protein encoded by this gene is a component of an E3 ubiquitin-protein ligase complex. The encoded protein interacts with TP53, CUL9, and FBXW8 proteins. Defects in this gene are a cause of 3M syndrome type 1 (3M1). Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2009]

CUL7 links:

ENSG00000288564 (HGNC:):

ENSG00000288564 links:

KLC4 (HGNC:21624): (kinesin light chain 4) Predicted to be located in cytoplasm and microtubule. Predicted to be part of kinesin complex. [provided by Alliance of Genome Resources, Apr 2022]

KLC4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002896458).

BP6

Variant 6-43051174-G-A is Benign according to our data. Variant chr6-43051174-G-A is described in ClinVar as Benign. ClinVar VariationId is 356852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0126 (1917/152292) while in subpopulation AFR AF = 0.0431 (1791/41550). AF 95% confidence interval is 0.0414. There are 44 homozygotes in GnomAd4. There are 931 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 44 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUL7	NM_014780.5 link	c.1027C>T	p.Pro343Ser	missense_variant	Exon 4 of 26	ENST00000265348.9	NP_055595.2	Q14999-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CUL7	ENST00000265348.9 link	c.1027C>T	p.Pro343Ser	missense_variant	Exon 4 of 26	1	NM_014780.5	ENSP00000265348.4	Q14999-1
ENSG00000288564	ENST00000673761.1 link	n.*1061C>T		non_coding_transcript_exon_variant	Exon 9 of 9			ENSP00000501018.1	A0A669KAX9
ENSG00000288564	ENST00000673761.1 link	n.*1061C>T		3_prime_UTR_variant	Exon 9 of 9			ENSP00000501018.1	A0A669KAX9

Frequencies

GnomAD3 genomes

AF:

0.0126

AC:

1910

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0431

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00635

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00669

GnomAD2 exomes

AF:

0.00321

AC:

807

AN:

251348

AF XY:

0.00256

show subpopulations

Gnomad AFR exome

AF:

0.0429

Gnomad AMR exome

AF:

0.00231

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000968

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.00121

AC:

1774

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00109

AC XY:

792

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.0412

AC:

1379

AN:

33480

American (AMR)

AF:

0.00259

AC:

116

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000325

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00364

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000270

AC:

AN:

1112010

Other (OTH)

AF:

0.00331

AC:

200

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

118

235

353

470

588

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

168

210

<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:

0.0126

AC:

1917

AN:

152292

Hom.:

Cov.:

AF XY:

0.0125

AC XY:

931

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.0431

AC:

1791

AN:

41550

American (AMR)

AF:

0.00634

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00104

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68026

Other (OTH)

AF:

0.00662

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

195

293

390

488

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.00434

Hom.:

Bravo

AF:

0.0143

ESP6500AA

AF:

0.0397

AC:

175

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00392

AC:

476

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 23, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

3M syndrome 1

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.58

D;.

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.70

T;T

MetaRNN

Benign

0.0029

T;T

MetaSVM

Uncertain

-0.26

MutationAssessor

Uncertain

2.3

M;.

PhyloP100

3.5

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-2.9

D;D

REVEL

Benign

0.21

Sift

Uncertain

0.0050

D;D

Sift4G

Uncertain

0.029

D;D

Polyphen

0.99

D;.

Vest4

0.16

MVP

0.84

MPC

0.22

ClinPred

0.044

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.14

gMVP

0.25

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over