17-36195362-C-T

Position:

• chr17-36195362-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2 BP4_Strong BP6_Moderate BS1

The NM_001001437.4(CCL3L3):​c.206G>A​(p.Arg69Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00571 in 146,936 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0057 (0 hom., cov: 38)
  • Exomes 𝑓: 0.00024 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CCL3L3 NM_001001437.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.14

Genes affected

CCL3L3 (HGNC:30554): (C-C motif chemokine ligand 3 like 3) This gene is one of several cytokine genes that are clustered on the q-arm of chromosome 17. Cytokines are a family of secreted proteins that function in inflammatory and immunoregulatory processes. The protein encoded by this gene binds to several chemokine receptors, including chemokine binding protein 2 and chemokine (C-C motif) receptor 5 (CCR5). CCR5 is a co-receptor for HIV, and binding of this protein to CCR5 inhibits HIV entry. The copy number of this gene varies among individuals, where most individuals have one to six copies, and a minority of individuals have zero or more than six copies. There are conflicting reports about copy number variation of this gene and its correlation to disease susceptibility.[provided by RefSeq, Apr 2014]

CCL3L3 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PM2: Variant has high frequency in the AFR(0.00635193) population. However there is too low homozygotes in high coverage region: (expected more than 1, got 0).
• BP4: Computational evidence support a benign effect (MetaRNN=0.007639587).
• BP6: Variant 17-36195362-C-T is Benign according to our data. Variant chr17-36195362-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2321914.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00571 (839/146936) while in subpopulation AFR AF= 0.0204 (808/39578). AF 95% confidence interval is 0.0192. There are 0 homozygotes in gnomad4. There are 401 alleles in male gnomad4 subpopulation. Median coverage is 38. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCL3L3	NM_001001437.4	c.206G>A	p.Arg69Lys	missense_variant	3/3	ENST00000619989.1	NP_001001437.2
LOC128966706	XR_008485584.1	n.313-768C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCL3L3	ENST00000619989.1	c.206G>A	p.Arg69Lys	missense_variant	3/3	1	NM_001001437.4	ENSP00000480558.1

Frequencies

GnomAD3 genomes AF: 0.00573 AC: 842 AN: 146822 Hom.: 0 Cov.: 38

Gnomad AFR AF: 0.0206

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00141

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000603

Gnomad OTH AF: 0.00296

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000240 AC: 344 AN: 1431608 Hom.: 0 Cov.: 38 AF XY: 0.000212 AC XY: 151 AN XY: 712114

Gnomad4 AFR exome AF: 0.00712

Gnomad4 AMR exome AF: 0.00106

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000355

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000211

Gnomad4 OTH exome AF: 0.000763

GnomAD4 genome AF: 0.00571 AC: 839 AN: 146936 Hom.: 0 Cov.: 38 AF XY: 0.00559 AC XY: 401 AN XY: 71698

Gnomad4 AFR AF: 0.0204

Gnomad4 AMR AF: 0.00141

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000603

Gnomad4 OTH AF: 0.00293

Alfa AF: 0.00767 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 01, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.017
DANN	Benign	0.85
DEOGEN2	Benign	0.038	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0046	N
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.0076	T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	D;N
Sift4G	Benign	1.0	T
Polyphen		0.0030	B
Vest4		0.090
MutPred		0.41		Gain of methylation at R69 (P = 0.025);
MVP		0.040
ClinPred		0.024	T
GERP RS		0.49
Varity_R		0.037
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1256855235; hg19: chr17-34522761;