6-43040677-G-C

Variant names:

• chr6-43040677-G-C
• rs147056081
• NM_014780.5:c.3876C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014780.5(CUL7):​c.3876C>G​(p.Ile1292Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I1292I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CUL7 NM_014780.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.923
• 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]

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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUL7	NM_014780.5	c.3876C>G	p.Ile1292Met	missense_variant	Exon 21 of 26	ENST00000265348.9	NP_055595.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUL7	ENST00000265348.9	c.3876C>G	p.Ile1292Met	missense_variant	Exon 21 of 26	1	NM_014780.5	ENSP00000265348.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461876 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	12
DANN	Uncertain	0.97
DEOGEN2	Benign	0.32	T;.
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.30	N
LIST_S2	Uncertain	0.91	D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.58	D;D
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.9	M;.
PhyloP100		-0.92
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.8	N;N
REVEL	Uncertain	0.60
Sift	Uncertain	0.0010	D;D
Sift4G	Benign	0.095	T;T
Vest4		0.58
ClinPred		0.96	D
GERP RS		-2.0
PromoterAI		-0.095	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.30
gMVP		0.45
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs147056081; hg19: chr6-43008415;