chr6-43038278-G-T

Variant names:

• chr6-43038278-G-T
• rs147493246
• NM_014780.5:c.4762C>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM5 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014780.5(CUL7):​c.4762C>A​(p.Leu1588Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00853 in 1,614,146 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1588P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0071 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0087 (64 hom.)
• Consequence: CUL7 NM_014780.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.88
• Publications: 12 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]

CUL7 Gene-Disease associations (from GenCC):

• 3M syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• 3-M syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-43038277-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 998007.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.010615438).
• BP6: Variant 6-43038278-G-T is Benign according to our data. Variant chr6-43038278-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 195895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00707 (1076/152290) while in subpopulation AMR AF = 0.00981 (150/15290). AF 95% confidence interval is 0.00916. There are 7 homozygotes in GnomAd4. There are 540 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUL7	NM_014780.5	MANE Select	c.4762C>A	p.Leu1588Ile	missense	Exon 25 of 26	NP_055595.2
	CUL7	NM_001168370.2		c.4858C>A	p.Leu1620Ile	missense	Exon 25 of 26	NP_001161842.2	A0A669KBH4
	CUL7	NM_001374872.1		c.4858C>A	p.Leu1620Ile	missense	Exon 25 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.4762C>A	p.Leu1588Ile	missense	Exon 25 of 26	ENSP00000265348.4	Q14999-1
	CUL7	ENST00000674100.1		c.4858C>A	p.Leu1620Ile	missense	Exon 25 of 26	ENSP00000501292.1	A0A669KBH4
	CUL7	ENST00000674134.1		c.4858C>A	p.Leu1620Ile	missense	Exon 25 of 26	ENSP00000501068.1	A0A669KBH4

Frequencies

GnomAD3 genomes AF: 0.00707 AC: 1076 AN: 152172 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00164

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00982

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0129

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00978

Gnomad OTH AF: 0.0148

GnomAD2 exomes AF: 0.00793 AC: 1987 AN: 250700 AF XY: 0.00773

Gnomad AFR exome AF: 0.00136

Gnomad AMR exome AF: 0.00637

Gnomad ASJ exome AF: 0.00537

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0162

Gnomad NFE exome AF: 0.0112

Gnomad OTH exome AF: 0.0103

GnomAD4 exome AF: 0.00868 AC: 12691 AN: 1461856 Hom.: 64 Cov.: 32 AF XY: 0.00858 AC XY: 6239 AN XY: 727226

African (AFR) AF: 0.00122 AC: 41 AN: 33480

American (AMR) AF: 0.00704 AC: 315 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00539 AC: 141 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000533 AC: 46 AN: 86256

European-Finnish (FIN) AF: 0.0169 AC: 901 AN: 53410

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5768

European-Non Finnish (NFE) AF: 0.00965 AC: 10735 AN: 1111994

Other (OTH) AF: 0.00825 AC: 498 AN: 60396

GnomAD4 genome AF: 0.00707 AC: 1076 AN: 152290 Hom.: 7 Cov.: 32 AF XY: 0.00725 AC XY: 540 AN XY: 74460

African (AFR) AF: 0.00166 AC: 69 AN: 41572

American (AMR) AF: 0.00981 AC: 150 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.0129 AC: 137 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00978 AC: 665 AN: 68020

Other (OTH) AF: 0.0147 AC: 31 AN: 2110

Alfa AF: 0.00921 Hom.: 21

Bravo AF: 0.00668

TwinsUK AF: 0.0121 AC: 45

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00907 AC: 78

ExAC AF: 0.00799 AC: 970

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00987

EpiControl AF: 0.0107

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	3M syndrome 1 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	0.56	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		4.9
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.59
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.62
MVP		0.92
MPC		0.80
ClinPred		0.032	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.29
gMVP		0.50
Mutation Taster		=95/5	polymorphism

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: rs147493246; hg19: chr6-43006016;