rs4711738

Positions:

• chr6-43052450-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_014780.5(CUL7):​c.339C>T​(p.Asp113=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.127 in 1,613,918 control chromosomes in the GnomAD database, including 19,808 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (5940 hom., cov: 32)
  • Exomes 𝑓: 0.12 (13868 hom.)
• Consequence: CUL7 NM_014780.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.04

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 6-43052450-G-A is Benign according to our data. Variant chr6-43052450-G-A is described in ClinVar as [Benign]. Clinvar id is 260438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-43052450-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.04 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.48 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CUL7	NM_014780.5	c.339C>T	p.Asp113=	synonymous_variant	2/26	ENST00000265348.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUL7	ENST00000265348.9	c.339C>T	p.Asp113=	synonymous_variant	2/26	1	NM_014780.5	P3

Frequencies

GnomAD3 genomes AF: 0.221 AC: 33616 AN: 152084 Hom.: 5919 Cov.: 32

Gnomad AFR AF: 0.485

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.195

Gnomad ASJ AF: 0.0978

Gnomad EAS AF: 0.241

Gnomad SAS AF: 0.204

Gnomad FIN AF: 0.0886

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.0959

Gnomad OTH AF: 0.217

GnomAD3 exomes AF: 0.158 AC: 39636 AN: 251342 Hom.: 4641 AF XY: 0.149 AC XY: 20213 AN XY: 135846

Gnomad AFR exome AF: 0.500

Gnomad AMR exome AF: 0.203

Gnomad ASJ exome AF: 0.0951

Gnomad EAS exome AF: 0.247

Gnomad SAS exome AF: 0.178

Gnomad FIN exome AF: 0.0869

Gnomad NFE exome AF: 0.0952

Gnomad OTH exome AF: 0.138

GnomAD4 exome AF: 0.117 AC: 171549 AN: 1461716 Hom.: 13868 Cov.: 35 AF XY: 0.117 AC XY: 85263 AN XY: 727122

Gnomad4 AFR exome AF: 0.499

Gnomad4 AMR exome AF: 0.204

Gnomad4 ASJ exome AF: 0.0968

Gnomad4 EAS exome AF: 0.240

Gnomad4 SAS exome AF: 0.171

Gnomad4 FIN exome AF: 0.0892

Gnomad4 NFE exome AF: 0.0940

Gnomad4 OTH exome AF: 0.147

GnomAD4 genome AF: 0.221 AC: 33682 AN: 152202 Hom.: 5940 Cov.: 32 AF XY: 0.220 AC XY: 16365 AN XY: 74422

Gnomad4 AFR AF: 0.485

Gnomad4 AMR AF: 0.195

Gnomad4 ASJ AF: 0.0978

Gnomad4 EAS AF: 0.240

Gnomad4 SAS AF: 0.202

Gnomad4 FIN AF: 0.0886

Gnomad4 NFE AF: 0.0960

Gnomad4 OTH AF: 0.222

Alfa AF: 0.129 Hom.: 2813

Bravo AF: 0.243

Asia WGS AF: 0.263 AC: 914 AN: 3478

EpiCase AF: 0.0948

EpiControl AF: 0.0952

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.89
DANN	Benign	0.75

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: rs4711738; hg19: chr6-43020188; COSMIC: COSV54813228; COSMIC: COSV54813228;