rs2273917

Variant names:

• chr6-43040560-C-T
• rs2273917
• NM_014780.5:c.3993G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_014780.5(CUL7):​c.3993G>A​(p.Leu1331Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.169 in 1,613,972 control chromosomes in the GnomAD database, including 31,149 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L1331L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.27 (8444 hom., cov: 32)
  • Exomes 𝑓: 0.16 (22705 hom.)
• Consequence: CUL7 NM_014780.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.668
• Publications: 25 publications found

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

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 6-43040560-C-T is Benign according to our data. Variant chr6-43040560-C-T is described in ClinVar as Benign. ClinVar VariationId is 260441.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.668 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.571 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUL7	NM_014780.5	MANE Select	c.3993G>A	p.Leu1331Leu	synonymous	Exon 21 of 26	NP_055595.2
	CUL7	NM_001168370.2		c.4089G>A	p.Leu1363Leu	synonymous	Exon 21 of 26	NP_001161842.2	A0A669KBH4
	CUL7	NM_001374872.1		c.4089G>A	p.Leu1363Leu	synonymous	Exon 21 of 26	NP_001361801.1	A0A669KBH4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUL7	ENST00000265348.9	TSL:1 MANE Select	c.3993G>A	p.Leu1331Leu	synonymous	Exon 21 of 26	ENSP00000265348.4	Q14999-1
	CUL7	ENST00000674100.1		c.4089G>A	p.Leu1363Leu	synonymous	Exon 21 of 26	ENSP00000501292.1	A0A669KBH4
	CUL7	ENST00000674134.1		c.4089G>A	p.Leu1363Leu	synonymous	Exon 21 of 26	ENSP00000501068.1	A0A669KBH4

Frequencies

GnomAD3 genomes AF: 0.270 AC: 41072 AN: 152050 Hom.: 8432 Cov.: 32

Gnomad AFR AF: 0.577

Gnomad AMI AF: 0.0647

Gnomad AMR AF: 0.217

Gnomad ASJ AF: 0.113

Gnomad EAS AF: 0.256

Gnomad SAS AF: 0.251

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.134

Gnomad OTH AF: 0.242

GnomAD2 exomes AF: 0.193 AC: 48599 AN: 251378 AF XY: 0.185

Gnomad AFR exome AF: 0.593

Gnomad AMR exome AF: 0.215

Gnomad ASJ exome AF: 0.106

Gnomad EAS exome AF: 0.264

Gnomad FIN exome AF: 0.111

Gnomad NFE exome AF: 0.133

Gnomad OTH exome AF: 0.173

GnomAD4 exome AF: 0.158 AC: 230888 AN: 1461804 Hom.: 22705 Cov.: 35 AF XY: 0.158 AC XY: 114959 AN XY: 727206

African (AFR) AF: 0.591 AC: 19793 AN: 33480

American (AMR) AF: 0.218 AC: 9756 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 2846 AN: 26136

East Asian (EAS) AF: 0.257 AC: 10219 AN: 39700

South Asian (SAS) AF: 0.225 AC: 19424 AN: 86258

European-Finnish (FIN) AF: 0.115 AC: 6119 AN: 53392

Middle Eastern (MID) AF: 0.162 AC: 934 AN: 5768

European-Non Finnish (NFE) AF: 0.136 AC: 150717 AN: 1111958

Other (OTH) AF: 0.183 AC: 11080 AN: 60388

GnomAD4 genome AF: 0.270 AC: 41127 AN: 152168 Hom.: 8444 Cov.: 32 AF XY: 0.267 AC XY: 19884 AN XY: 74406

African (AFR) AF: 0.577 AC: 23944 AN: 41492

American (AMR) AF: 0.217 AC: 3318 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 393 AN: 3470

East Asian (EAS) AF: 0.255 AC: 1320 AN: 5170

South Asian (SAS) AF: 0.249 AC: 1202 AN: 4824

European-Finnish (FIN) AF: 0.111 AC: 1178 AN: 10612

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.134 AC: 9133 AN: 67994

Other (OTH) AF: 0.246 AC: 518 AN: 2108

Alfa AF: 0.181 Hom.: 6060

Bravo AF: 0.294

Asia WGS AF: 0.290 AC: 1007 AN: 3478

EpiCase AF: 0.131

EpiControl AF: 0.130

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	3M syndrome 1 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	8.7
DANN	Benign	0.80
PhyloP100		0.67
PromoterAI		-0.017	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2273917; hg19: chr6-43008298; COSMIC: COSV54814346; COSMIC: COSV54814346;