Genetic Variant CUL7:p.Gly287Gly (chr6-43051340-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_014780.5(CUL7):c.861G>A(p.Gly287Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00234 in 1,611,870 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0024 ( 9 hom. )

Consequence

CUL7
NM_014780.5 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 0.0250

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 6-43051340-C-T is Benign according to our data. Variant chr6-43051340-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 260442.

BP7

Synonymous conserved (PhyloP=0.025 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00146 (222/152224) while in subpopulation SAS AF = 0.00332 (16/4822). AF 95% confidence interval is 0.00222. There are 0 homozygotes in GnomAd4. There are 100 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 9 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.861G>A	p.Gly287Gly	synonymous	Exon 4 of 26	NP_055595.2
CUL7	NM_001168370.2		c.957G>A	p.Gly319Gly	synonymous	Exon 4 of 26	NP_001161842.2	A0A669KBH4
CUL7	NM_001374872.1		c.957G>A	p.Gly319Gly	synonymous	Exon 4 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.861G>A	p.Gly287Gly	synonymous	Exon 4 of 26	ENSP00000265348.4	Q14999-1
ENSG00000288564	ENST00000673761.1		n.*895G>A		non_coding_transcript_exon	Exon 9 of 9	ENSP00000501018.1	A0A669KAX9
ENSG00000288564	ENST00000673761.1		n.*895G>A		3_prime_UTR	Exon 9 of 9	ENSP00000501018.1	A0A669KAX9

Frequencies

GnomAD3 genomes

AF:

0.00146

AC:

222

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000459

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000786

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00332

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00253

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00149

AC:

373

AN:

250568

AF XY:

0.00160

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.000696

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00232

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.00243

AC:

3554

AN:

1459646

Hom.:

Cov.:

AF XY:

0.00245

AC XY:

1776

AN XY:

725758

show subpopulations

African (AFR)

AF:

0.000389

AC:

AN:

33382

American (AMR)

AF:

0.000762

AC:

AN:

44602

Ashkenazi Jewish (ASJ)

AF:

0.0000384

AC:

AN:

26018

East Asian (EAS)

AF:

0.00

AC:

AN:

39650

South Asian (SAS)

AF:

0.00245

AC:

211

AN:

86184

European-Finnish (FIN)

AF:

0.000150

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00285

AC:

3170

AN:

1110382

Other (OTH)

AF:

0.00183

AC:

110

AN:

60274

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

207

414

620

827

1034

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

130

260

390

520

650

<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:

0.00146

AC:

222

AN:

152224

Hom.:

Cov.:

AF XY:

0.00134

AC XY:

100

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.000457

AC:

AN:

41540

American (AMR)

AF:

0.000785

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00332

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00253

AC:

172

AN:

68008

Other (OTH)

AF:

0.00142

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

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:

0.00185

Hom.:

Bravo

AF:

0.00137

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00267

EpiControl

AF:

0.00243

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

not provided (2)

3M syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

3.3

(source)

DANN

Benign

0.75

PhyloP100

0.025

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(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