6-43046561-T-C

Variant names:

Variant summary

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

The NM_014780.5(CUL7):c.2438A>G(p.Gln813Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.972 in 1,614,046 control chromosomes in the GnomAD database, including 762,334 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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. Q813Q) has been classified as Benign.

Frequency

Genomes: 𝑓 0.98 ( 73002 hom., cov: 31)

Exomes 𝑓: 0.97 ( 689332 hom. )

Consequence

CUL7
NM_014780.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.49

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:

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 made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=6.3990467E-7).

BP6

Variant 6-43046561-T-C is Benign according to our data. Variant chr6-43046561-T-C is described in ClinVar as [Benign]. Clinvar id is 260436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-43046561-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.986 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUL7	NM_014780.5 link	c.2438A>G	p.Gln813Arg	missense_variant	Exon 11 of 26	ENST00000265348.9	NP_055595.2	Q14999-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUL7	ENST00000265348.9 link	c.2438A>G	p.Gln813Arg	missense_variant	Exon 11 of 26	1	NM_014780.5	ENSP00000265348.4		Q14999-1

Frequencies

GnomAD3 genomes

AF:

0.979

AC:

148924

AN:

152112

Hom.:

72939

Cov.:

show subpopulations

Gnomad AFR

AF:

0.994

Gnomad AMI

AF:

0.993

Gnomad AMR

AF:

0.982

Gnomad ASJ

AF:

0.895

Gnomad EAS

AF:

0.999

Gnomad SAS

AF:

0.988

Gnomad FIN

AF:

0.995

Gnomad MID

AF:

0.949

Gnomad NFE

AF:

0.969

Gnomad OTH

AF:

0.973

GnomAD3 exomes

AF:

0.976

AC:

245330

AN:

251312

Hom.:

119808

AF XY:

0.975

AC XY:

132452

AN XY:

135806

show subpopulations

Gnomad AFR exome

AF:

0.995

Gnomad AMR exome

AF:

0.985

Gnomad ASJ exome

AF:

0.894

Gnomad EAS exome

AF:

1.00

Gnomad SAS exome

AF:

0.989

Gnomad FIN exome

AF:

0.992

Gnomad NFE exome

AF:

0.968

Gnomad OTH exome

AF:

0.971

GnomAD4 exome

AF:

0.971

AC:

1419455

AN:

1461816

Hom.:

689332

Cov.:

120

AF XY:

0.971

AC XY:

706131

AN XY:

727194

show subpopulations

Gnomad4 AFR exome

AF:

0.995

Gnomad4 AMR exome

AF:

0.983

Gnomad4 ASJ exome

AF:

0.891

Gnomad4 EAS exome

AF:

0.999

Gnomad4 SAS exome

AF:

0.989

Gnomad4 FIN exome

AF:

0.992

Gnomad4 NFE exome

AF:

0.969

Gnomad4 OTH exome

AF:

0.970

GnomAD4 genome

AF:

0.979

AC:

149046

AN:

152230

Hom.:

73002

Cov.:

AF XY:

0.981

AC XY:

73033

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.994

Gnomad4 AMR

AF:

0.982

Gnomad4 ASJ

AF:

0.895

Gnomad4 EAS

AF:

1.00

Gnomad4 SAS

AF:

0.988

Gnomad4 FIN

AF:

0.995

Gnomad4 NFE

AF:

0.969

Gnomad4 OTH

AF:

0.973

Alfa

AF:

0.967

Hom.:

33196

Bravo

AF:

0.978

TwinsUK

AF:

0.972

AC:

3603

ALSPAC

AF:

0.969

AC:

3735

ESP6500AA

AF:

0.995

AC:

4382

ESP6500EA

AF:

0.968

AC:

8323

ExAC

AF:

0.976

AC:

118544

Asia WGS

AF:

0.992

AC:

3449

AN:

3478

EpiCase

AF:

0.969

EpiControl

AF:

0.964

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

3M syndrome 1

Benign:2

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. -

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Nov 10, 2018

GeneDx

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

0.059

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.63

CADD

Benign

DANN

Benign

0.69

DEOGEN2

Benign

0.11

T;.

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.24

T;T

MetaRNN

Benign

6.4e-7

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.46

N;.

PrimateAI

Benign

0.35

PROVEAN

Benign

0.31

N;N

REVEL

Benign

0.087

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;.

Vest4

0.088

MPC

0.21

ClinPred

0.000019

GERP RS

1.6

Varity_R

0.022

gMVP

0.19

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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