rs4711738

Variant names:

• chr6-43052450-G-A
• rs4711738
• NM_014780.5:c.339C>T

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.339C>T​(p.Asp113Asp) 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
• Publications: 17 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]

ENSG00000288564 (HGNC:):

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=-0.81).
• BP6: Variant 6-43052450-G-A is Benign according to our data. Variant chr6-43052450-G-A is described in ClinVar as Benign. ClinVar VariationId is 260438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
CUL7	NM_014780.5	c.339C>T	p.Asp113Asp	synonymous_variant	Exon 2 of 26	ENST00000265348.9	NP_055595.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUL7	ENST00000265348.9	c.339C>T	p.Asp113Asp	synonymous_variant	Exon 2 of 26	1	NM_014780.5	ENSP00000265348.4
ENSG00000288564	ENST00000673761.1	n.*263C>T		non_coding_transcript_exon_variant	Exon 7 of 9			ENSP00000501018.1
ENSG00000288564	ENST00000673761.1	n.*263C>T		3_prime_UTR_variant	Exon 7 of 9			ENSP00000501018.1

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

GnomAD2 exomes AF: 0.158 AC: 39636 AN: 251342 AF XY: 0.149

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 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

African (AFR) AF: 0.499 AC: 16704 AN: 33476

American (AMR) AF: 0.204 AC: 9143 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0968 AC: 2529 AN: 26136

East Asian (EAS) AF: 0.240 AC: 9519 AN: 39698

South Asian (SAS) AF: 0.171 AC: 14708 AN: 86258

European-Finnish (FIN) AF: 0.0892 AC: 4763 AN: 53386

Middle Eastern (MID) AF: 0.142 AC: 819 AN: 5768

European-Non Finnish (NFE) AF: 0.0940 AC: 104492 AN: 1111886

Other (OTH) AF: 0.147 AC: 8872 AN: 60388

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

African (AFR) AF: 0.485 AC: 20139 AN: 41500

American (AMR) AF: 0.195 AC: 2982 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0978 AC: 339 AN: 3468

East Asian (EAS) AF: 0.240 AC: 1242 AN: 5176

South Asian (SAS) AF: 0.202 AC: 976 AN: 4824

European-Finnish (FIN) AF: 0.0886 AC: 941 AN: 10618

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.0960 AC: 6526 AN: 68012

Other (OTH) AF: 0.222 AC: 469 AN: 2114

Alfa AF: 0.143 Hom.: 4780

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

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

3M syndrome 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-2.0
PromoterAI		-0.034	Neutral
Mutation Taster		=99/1	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: rs4711738; hg19: chr6-43020188; COSMIC: COSV54813228; COSMIC: COSV54813228;