6-43037697-G-C

Variant names:

• chr6-43037697-G-C
• rs73733789
• NM_014780.5:c.5088C>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_014780.5(CUL7):​c.5088C>G​(p.Thr1696Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000713 in 1,403,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. T1696T) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: CUL7 NM_014780.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.159
• Publications: 0 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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP7: Synonymous conserved (PhyloP=-0.159 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUL7	NM_014780.5	c.5088C>G	p.Thr1696Thr	synonymous_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.5088C>G	p.Thr1696Thr	synonymous_variant	Exon 26 of 26	1	NM_014780.5	ENSP00000265348.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.13e-7 AC: 1 AN: 1403034 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 692382

African (AFR) AF: 0.00 AC: 0 AN: 31912

American (AMR) AF: 0.00 AC: 0 AN: 35892

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25190

East Asian (EAS) AF: 0.00 AC: 0 AN: 36168

South Asian (SAS) AF: 0.00 AC: 0 AN: 79510

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5686

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1080926

Other (OTH) AF: 0.0000172 AC: 1 AN: 58156

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	3.8
DANN	Benign	0.59
PhyloP100		-0.16
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs73733789; hg19: chr6-43005435;