6-43041026-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_014780.5(CUL7):c.3695G>A(p.Arg1232Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0015 in 1,613,856 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (45 hom.)
• Consequence: CUL7 NM_014780.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.62

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]

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]

LOC124901318 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0048012733).
• BP6: Variant 6-43041026-C-T is Benign according to our data. Variant chr6-43041026-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 281912.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CUL7	NM_014780.5	c.3695G>A	p.Arg1232Gln	missense_variant	20/26	ENST00000265348.9
LOC124901318	XR_007059581.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUL7	ENST00000265348.9	c.3695G>A	p.Arg1232Gln	missense_variant	20/26	1	NM_014780.5	P3

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 224 AN: 152208 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.0521

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00277 AC: 695 AN: 250760 Hom.: 17 AF XY: 0.00265 AC XY: 359 AN XY: 135538

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.0576

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000670

Gnomad OTH exome AF: 0.00589

GnomAD4 exome AF: 0.00150 AC: 2196 AN: 1461648 Hom.: 45 Cov.: 32 AF XY: 0.00152 AC XY: 1106 AN XY: 727080

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.0584

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000339

Gnomad4 OTH exome AF: 0.00465

GnomAD4 genome AF: 0.00147 AC: 224 AN: 152208 Hom.: 3 Cov.: 32 AF XY: 0.00126 AC XY: 94 AN XY: 74348

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.0521

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000529

Gnomad4 OTH AF: 0.00143

Alfa AF: 0.00334 Hom.: 22

Bravo AF: 0.00164

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00267 AC: 23

ExAC AF: 0.00192 AC: 233

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00115

EpiControl AF: 0.00107

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 17, 2015

- -

CUL7-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 16, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

3M syndrome 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.22
Cadd	Uncertain	24
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.26	T;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.0048	T;T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Uncertain	2.6	M;.
MutationTaster	Benign	0.97	D;D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.7	N;N
REVEL	Uncertain	0.37
Sift	Benign	0.21	T;T
Sift4G	Benign	0.17	T;T
Polyphen		1.0	D;.
Vest4		0.38
MVP		0.84
MPC		0.61
ClinPred		0.046	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.088
gMVP		0.081

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

Other links and lift over

dbSNP: rs36004037; hg19: chr6-43008764;