rs61750322

Positions:

• chr6-43051340-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_014780.5(CUL7):​c.861G>A​(p.Gly287Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00234 in 1,611,870 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (9 hom.)
• Consequence: CUL7 NM_014780.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.0250

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

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 6-43051340-C-T is Benign according to our data. Variant chr6-43051340-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 260442.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=2}.
• BP7: Synonymous conserved (PhyloP=0.025 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00146 (222/152224) while in subpopulation SAS AF= 0.00332 (16/4822). AF 95% confidence interval is 0.00222. There are 0 homozygotes in gnomad4. There are 100 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CUL7	NM_014780.5	c.861G>A	p.Gly287Gly	synonymous_variant	4/26	ENST00000265348.9	NP_055595.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CUL7	ENST00000265348.9	c.861G>A	p.Gly287Gly	synonymous_variant	4/26	1	NM_014780.5	ENSP00000265348.4
ENSG00000288564	ENST00000673761.1	n.*895G>A		non_coding_transcript_exon_variant	9/9			ENSP00000501018.1
ENSG00000288564	ENST00000673761.1	n.*895G>A		3_prime_UTR_variant	9/9			ENSP00000501018.1

Frequencies

GnomAD3 genomes AF: 0.00146 AC: 222 AN: 152106 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00332

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00253

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00149 AC: 373 AN: 250568 Hom.: 0 AF XY: 0.00160 AC XY: 216 AN XY: 135422

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.000696

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00213

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00232

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00243 AC: 3554 AN: 1459646 Hom.: 9 Cov.: 34 AF XY: 0.00245 AC XY: 1776 AN XY: 725758

Gnomad4 AFR exome AF: 0.000389

Gnomad4 AMR exome AF: 0.000762

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00245

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.00285

Gnomad4 OTH exome AF: 0.00183

GnomAD4 genome AF: 0.00146 AC: 222 AN: 152224 Hom.: 0 Cov.: 32 AF XY: 0.00134 AC XY: 100 AN XY: 74416

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.000785

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00253

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00185 Hom.: 0

Bravo AF: 0.00137

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00267

EpiControl AF: 0.00243

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 16, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 25, 2016	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	CUL7: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 10, 2024	- -

3M syndrome 1 Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	3.3
DANN	Benign	0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs61750322; hg19: chr6-43019078;