Genetic Variant NM_014780.5:c.2614G>A (chr6-43046282-C-T) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_014780.5(CUL7):c.2614G>A(p.Gly872Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00238 in 1,614,188 control chromosomes in the GnomAD database, including 6 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. G872R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0025 ( 6 hom. )

Consequence

CUL7
NM_014780.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:4

Conservation

PhyloP100: 7.82

Publications

8 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:

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13558513).

BP6

Variant 6-43046282-C-T is Benign according to our data. Variant chr6-43046282-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 282333.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00163 (249/152314) while in subpopulation NFE AF = 0.00294 (200/68030). AF 95% confidence interval is 0.00261. There are 0 homozygotes in GnomAd4. There are 113 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014780.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CUL7	NM_014780.5	MANE Select	c.2614G>A	p.Gly872Ser	missense	Exon 12 of 26	NP_055595.2
CUL7	NM_001168370.2		c.2710G>A	p.Gly904Ser	missense	Exon 12 of 26	NP_001161842.2	A0A669KBH4
CUL7	NM_001374872.1		c.2710G>A	p.Gly904Ser	missense	Exon 12 of 26	NP_001361801.1	A0A669KBH4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CUL7	ENST00000265348.9	TSL:1 MANE Select	c.2614G>A	p.Gly872Ser	missense	Exon 12 of 26	ENSP00000265348.4	Q14999-1
CUL7	ENST00000674100.1		c.2710G>A	p.Gly904Ser	missense	Exon 12 of 26	ENSP00000501292.1	A0A669KBH4
CUL7	ENST00000674134.1		c.2710G>A	p.Gly904Ser	missense	Exon 12 of 26	ENSP00000501068.1	A0A669KBH4

Frequencies

GnomAD3 genomes

AF:

0.00164

AC:

249

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000579

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000981

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00294

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00151

AC:

379

AN:

251468

AF XY:

0.00159

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.00145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.000739

Gnomad NFE exome

AF:

0.00238

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00246

AC:

3592

AN:

1461874

Hom.:

Cov.:

AF XY:

0.00238

AC XY:

1731

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.000329

AC:

AN:

33480

American (AMR)

AF:

0.00125

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.000626

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.000655

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000521

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00297

AC:

3308

AN:

1112008

Other (OTH)

AF:

0.00189

AC:

114

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

248

496

745

993

1241

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

134

268

402

536

670

<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:

0.00163

AC:

249

AN:

152314

Hom.:

Cov.:

AF XY:

0.00152

AC XY:

113

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.000577

AC:

AN:

41572

American (AMR)

AF:

0.000980

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5170

South Asian (SAS)

AF:

0.000414

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00294

AC:

200

AN:

68030

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00224

Hom.:

Bravo

AF:

0.00157

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00233

AC:

ExAC

AF:

0.00139

AC:

169

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00262

EpiControl

AF:

0.00213

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

3M syndrome 1 (2)

CUL7-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.65

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.14

MetaSVM

Uncertain

-0.12

MutationAssessor

Pathogenic

3.1

PhyloP100

7.8

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-4.1

REVEL

Uncertain

0.45

Sift

Uncertain

0.0030

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.78

MVP

0.79

MPC

0.77

ClinPred

0.058

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.47

gMVP

0.55

Mutation Taster

=43/57

disease causing

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over