6-43041026-C-T

Variant names:

• chr6-43041026-C-T
• rs36004037
• NM_014780.5:c.3695G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 10 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]

LOC124901318 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 281912.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 3 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.3695G>A	p.Arg1232Gln	missense	Exon 20 of 26	NP_055595.2
	CUL7	NM_001168370.2		c.3791G>A	p.Arg1264Gln	missense	Exon 20 of 26	NP_001161842.2	A0A669KBH4
	CUL7	NM_001374872.1		c.3791G>A	p.Arg1264Gln	missense	Exon 20 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.3695G>A	p.Arg1232Gln	missense	Exon 20 of 26	ENSP00000265348.4	Q14999-1
	CUL7	ENST00000674100.1		c.3791G>A	p.Arg1264Gln	missense	Exon 20 of 26	ENSP00000501292.1	A0A669KBH4
	CUL7	ENST00000674134.1		c.3791G>A	p.Arg1264Gln	missense	Exon 20 of 26	ENSP00000501068.1	A0A669KBH4

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

GnomAD2 exomes AF: 0.00277 AC: 695 AN: 250760 AF XY: 0.00265

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 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

African (AFR) AF: 0.0000896 AC: 3 AN: 33476

American (AMR) AF: 0.0000671 AC: 3 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.0584 AC: 1526 AN: 26114

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86180

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53404

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5766

European-Non Finnish (NFE) AF: 0.000339 AC: 377 AN: 1111926

Other (OTH) AF: 0.00465 AC: 281 AN: 60390

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

African (AFR) AF: 0.0000965 AC: 4 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0521 AC: 181 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000529 AC: 36 AN: 68042

Other (OTH) AF: 0.00143 AC: 3 AN: 2092

Alfa AF: 0.00298 Hom.: 23

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	3M syndrome 1 (1)
-	-	1	CUL7-related disorder (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.0048	T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		1.6
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.37
Sift	Benign	0.21	T
Sift4G	Benign	0.17	T
Polyphen		1.0	D
Vest4		0.38
MVP		0.84
MPC		0.61
ClinPred		0.046	T
GERP RS		5.4
PromoterAI		-0.0035	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.088
gMVP		0.081
Mutation Taster		=96/4	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: rs36004037; hg19: chr6-43008764;