rs201135654

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_014780.5(CUL7):c.3490C>T(p.Arg1164Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000471 in 1,614,144 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1164Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00099 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00042 ( 8 hom. )

Consequence

CUL7
NM_014780.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 3.00

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:

LOC124901318 (HGNC:):

LOC124901318 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0089660585).

BP6

Variant 6-43042957-G-A is Benign according to our data. Variant chr6-43042957-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 194968.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=3}.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000992 (151/152268) while in subpopulation AMR AF= 0.00942 (144/15294). AF 95% confidence interval is 0.00816. There are 3 homozygotes in gnomad4. There are 88 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CUL7	NM_014780.5 linkuse as main transcript	c.3490C>T	p.Arg1164Trp	missense_variant	19/26	ENST00000265348.9
LOC124901318	XR_007059581.1 linkuse as main transcript	n.90-101G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUL7	ENST00000265348.9 linkuse as main transcript	c.3490C>T	p.Arg1164Trp	missense_variant	19/26	1	NM_014780.5	P3	Q14999-1

Frequencies

GnomAD3 genomes

AF:

0.000992

AC:

151

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00943

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00190

AC:

478

AN:

251384

Hom.:

AF XY:

0.00152

AC XY:

207

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.0135

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.000417

AC:

609

AN:

1461876

Hom.:

Cov.:

AF XY:

0.000360

AC XY:

262

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.0127

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.000364

GnomAD4 genome

AF:

0.000992

AC:

151

AN:

152268

Hom.:

Cov.:

AF XY:

0.00118

AC XY:

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.00942

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000102

Hom.:

Bravo

AF:

0.00142

ExAC

AF:

0.00128

AC:

156

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 04, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 26, 2017	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 21, 2015

- -

3M syndrome 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

0.13

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.30

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Uncertain

0.60

D;.

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.89

D;D

MetaRNN

Benign

0.0090

T;T

MetaSVM

Benign

-0.29

MutationAssessor

Uncertain

2.5

M;.

MutationTaster

Benign

0.69

D;D

PrimateAI

Benign

0.28

PROVEAN

Uncertain

-3.0

D;D

REVEL

Uncertain

0.51

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0060

D;D

Polyphen

1.0

D;.

Vest4

0.41

MVP

0.86

MPC

0.66

ClinPred

0.13

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.15

gMVP

0.24

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