chr6-43037631-T-C

Variant names:

• chr6-43037631-T-C
• rs565386041
• NM_014780.5:c.*57A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_014780.5(CUL7):​c.*57A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000252 in 1,454,592 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00038 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (1 hom.)
• Consequence: CUL7 NM_014780.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.432
• Publications: 1 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 3-M syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000381 (58/152276) while in subpopulation SAS AF = 0.00124 (6/4828). AF 95% confidence interval is 0.00056. There are 1 homozygotes in GnomAd4. There are 30 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUL7	NM_014780.5	c.*57A>G		3_prime_UTR_variant	Exon 26 of 26	ENST00000265348.9	NP_055595.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUL7	ENST00000265348.9	c.*57A>G		3_prime_UTR_variant	Exon 26 of 26	1	NM_014780.5	ENSP00000265348.4

Frequencies

GnomAD3 genomes AF: 0.000381 AC: 58 AN: 152158 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00143

GnomAD4 exome AF: 0.000237 AC: 309 AN: 1302316 Hom.: 1 Cov.: 21 AF XY: 0.000220 AC XY: 142 AN XY: 646902

African (AFR) AF: 0.00156 AC: 46 AN: 29466

American (AMR) AF: 0.000816 AC: 29 AN: 35540

Ashkenazi Jewish (ASJ) AF: 0.000203 AC: 5 AN: 24572

East Asian (EAS) AF: 0.00 AC: 0 AN: 35230

South Asian (SAS) AF: 0.000466 AC: 36 AN: 77188

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48096

Middle Eastern (MID) AF: 0.00147 AC: 8 AN: 5426

European-Non Finnish (NFE) AF: 0.000138 AC: 137 AN: 992222

Other (OTH) AF: 0.000880 AC: 48 AN: 54576

GnomAD4 genome AF: 0.000381 AC: 58 AN: 152276 Hom.: 1 Cov.: 32 AF XY: 0.000403 AC XY: 30 AN XY: 74456

African (AFR) AF: 0.000770 AC: 32 AN: 41556

American (AMR) AF: 0.000327 AC: 5 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68014

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.000277 Hom.: 0

Bravo AF: 0.000453

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

3M syndrome 1 Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, 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. -

not provided Uncertain:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.89
DANN	Benign	0.48
PhyloP100		-0.43
Mutation Taster		=100/0	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: rs565386041; hg19: chr6-43005369;