rs147056081

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr6-43040677-G-A
• chr6-43040677-G-C
• chr6-43040677-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_014780.5(CUL7):​c.3876C>T​(p.Ile1292Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000528 in 1,614,192 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (2 hom.)
• Consequence: CUL7 NM_014780.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.923
• Publications: 2 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 6-43040677-G-A is Benign according to our data. Variant chr6-43040677-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.923 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000512 (78/152316) while in subpopulation EAS AF = 0.00541 (28/5180). AF 95% confidence interval is 0.00384. There are 0 homozygotes in GnomAd4. There are 33 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014780.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUL7	NM_014780.5	MANE Select	c.3876C>T	p.Ile1292Ile	synonymous	Exon 21 of 26	NP_055595.2
	CUL7	NM_001168370.2		c.3972C>T	p.Ile1324Ile	synonymous	Exon 21 of 26	NP_001161842.2	A0A669KBH4
	CUL7	NM_001374872.1		c.3972C>T	p.Ile1324Ile	synonymous	Exon 21 of 26	NP_001361801.1	A0A669KBH4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUL7	ENST00000265348.9	TSL:1 MANE Select	c.3876C>T	p.Ile1292Ile	synonymous	Exon 21 of 26	ENSP00000265348.4	Q14999-1
	CUL7	ENST00000674100.1		c.3972C>T	p.Ile1324Ile	synonymous	Exon 21 of 26	ENSP00000501292.1	A0A669KBH4
	CUL7	ENST00000674134.1		c.3972C>T	p.Ile1324Ile	synonymous	Exon 21 of 26	ENSP00000501068.1	A0A669KBH4

Frequencies

GnomAD3 genomes AF: 0.000512 AC: 78 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00539

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000892 AC: 224 AN: 251238 AF XY: 0.000817

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00636

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000581

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.000530 AC: 775 AN: 1461876 Hom.: 2 Cov.: 34 AF XY: 0.000558 AC XY: 406 AN XY: 727242

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.000291 AC: 13 AN: 44724

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

East Asian (EAS) AF: 0.00290 AC: 115 AN: 39700

South Asian (SAS) AF: 0.000661 AC: 57 AN: 86258

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53402

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.000494 AC: 549 AN: 1112012

Other (OTH) AF: 0.000563 AC: 34 AN: 60396

GnomAD4 genome AF: 0.000512 AC: 78 AN: 152316 Hom.: 0 Cov.: 32 AF XY: 0.000443 AC XY: 33 AN XY: 74478

African (AFR) AF: 0.0000722 AC: 3 AN: 41566

American (AMR) AF: 0.000196 AC: 3 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00541 AC: 28 AN: 5180

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4826

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000544 AC: 37 AN: 68028

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000549 Hom.: 0

Bravo AF: 0.000567

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000948

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	3M syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	7.4
DANN	Benign	0.88
PhyloP100		-0.92
PromoterAI		0.11	Neutral
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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; COSMIC: COSV54815842; COSMIC: COSV54815842;