chr6-43046560-T-C

Position:

• chr6-43046560-T-C

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.2439A>G​(p.Gln813=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.972 in 1,614,046 control chromosomes in the GnomAD database, including 762,366 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.98 (73000 hom., cov: 31)
  • Exomes 𝑓: 0.97 (689366 hom.)
• Consequence: CUL7 NM_014780.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.505

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=-0.63).
• BP6: Variant 6-43046560-T-C is Benign according to our data. Variant chr6-43046560-T-C is described in ClinVar as [Benign]. Clinvar id is 260437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-43046560-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.505 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.986 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CUL7	NM_014780.5	c.2439A>G	p.Gln813=	synonymous_variant	11/26	ENST00000265348.9	NP_055595.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CUL7	ENST00000265348.9	c.2439A>G	p.Gln813=	synonymous_variant	11/26	1	NM_014780.5	ENSP00000265348	P3

Frequencies

GnomAD3 genomes AF: 0.979 AC: 148920 AN: 152106 Hom.: 72938 Cov.: 31

Gnomad AFR AF: 0.994

Gnomad AMI AF: 0.993

Gnomad AMR AF: 0.982

Gnomad ASJ AF: 0.895

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.988

Gnomad FIN AF: 0.995

Gnomad MID AF: 0.949

Gnomad NFE AF: 0.969

Gnomad OTH AF: 0.973

GnomAD3 exomes AF: 0.976 AC: 245352 AN: 251320 Hom.: 119826 AF XY: 0.975 AC XY: 132464 AN XY: 135804

Gnomad AFR exome AF: 0.995

Gnomad AMR exome AF: 0.985

Gnomad ASJ exome AF: 0.894

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.989

Gnomad FIN exome AF: 0.992

Gnomad NFE exome AF: 0.968

Gnomad OTH exome AF: 0.971

GnomAD4 exome AF: 0.971 AC: 1419492 AN: 1461822 Hom.: 689366 Cov.: 119 AF XY: 0.971 AC XY: 706150 AN XY: 727196

Gnomad4 AFR exome AF: 0.995

Gnomad4 AMR exome AF: 0.983

Gnomad4 ASJ exome AF: 0.891

Gnomad4 EAS exome AF: 0.999

Gnomad4 SAS exome AF: 0.989

Gnomad4 FIN exome AF: 0.992

Gnomad4 NFE exome AF: 0.969

Gnomad4 OTH exome AF: 0.970

GnomAD4 genome AF: 0.979 AC: 149041 AN: 152224 Hom.: 73000 Cov.: 31 AF XY: 0.981 AC XY: 73031 AN XY: 74438

Gnomad4 AFR AF: 0.994

Gnomad4 AMR AF: 0.982

Gnomad4 ASJ AF: 0.895

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.988

Gnomad4 FIN AF: 0.995

Gnomad4 NFE AF: 0.969

Gnomad4 OTH AF: 0.973

Alfa AF: 0.966 Hom.: 25942

Bravo AF: 0.978

Asia WGS AF: 0.992 AC: 3449 AN: 3478

EpiCase AF: 0.969

EpiControl AF: 0.964

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

3M syndrome 1 Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 10, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	5.7
DANN	Benign	0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs9394939; hg19: chr6-43014298;