rs12721497

Positions:

• chr3-45901638-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_031200.3(CCR9):​c.850A>G​(p.Met284Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00186 in 1,614,184 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0054 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (12 hom.)
• Consequence: CCR9 NM_031200.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.438

Genes affected

CCR9 (HGNC:1610): (C-C motif chemokine receptor 9) The protein encoded by this gene is a G protein-coupled receptor with seven transmembrane domains that belongs to the beta chemokine receptor family. Chemokines and their receptors are key regulators of thymocyte migration and maturation in normal and inflammation conditions. This gene is differentially expressed in T lymphocytes of the small intestine and colon, and its interaction with chemokine 25 contributes to intestinal intra-epithelial lymphocyte homing to the small intestine. This suggests a role for this gene in directing immune responses to different segments of the gastrointestinal tract. This gene and its exclusive ligand, chemokine 25, are overexpressed in a variety of malignant tumors and are closely associated with tumor proliferation, apoptosis, invasion, migration and drug resistance. This gene maps to the chemokine receptor gene cluster. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2020]

LZTFL1 (HGNC:6741): (leucine zipper transcription factor like 1) This gene encodes a ubiquitously expressed protein that localizes to the cytoplasm. This protein interacts with Bardet-Biedl Syndrome (BBS) proteins and, through its interaction with BBS protein complexes, regulates protein trafficking to the ciliary membrane. Nonsense mutations in this gene cause a form of Bardet-Biedl Syndrome; a ciliopathy characterized in part by polydactyly, obesity, cognitive impairment, hypogonadism, and kidney failure. This gene may also function as a tumor suppressor; possibly by interacting with E-cadherin and the actin cytoskeleton and thereby regulating the transition of epithelial cells to mesenchymal cells. [provided by RefSeq, Aug 2020]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002496183).
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCR9	NM_031200.3	c.850A>G	p.Met284Val	missense_variant	3/3	ENST00000357632.7	NP_112477.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCR9	ENST00000357632.7	c.850A>G	p.Met284Val	missense_variant	3/3	1	NM_031200.3	ENSP00000350256	P1

Frequencies

GnomAD3 genomes AF: 0.00537 AC: 817 AN: 152220 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00235

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00712

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.00764

GnomAD3 exomes AF: 0.00297 AC: 747 AN: 251452 Hom.: 2 AF XY: 0.00274 AC XY: 373 AN XY: 135894

Gnomad AFR exome AF: 0.0169

Gnomad AMR exome AF: 0.00208

Gnomad ASJ exome AF: 0.00337

Gnomad EAS exome AF: 0.00680

Gnomad SAS exome AF: 0.00447

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000756

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00150 AC: 2186 AN: 1461846 Hom.: 12 Cov.: 33 AF XY: 0.00155 AC XY: 1128 AN XY: 727208

Gnomad4 AFR exome AF: 0.0146

Gnomad4 AMR exome AF: 0.00215

Gnomad4 ASJ exome AF: 0.00241

Gnomad4 EAS exome AF: 0.0126

Gnomad4 SAS exome AF: 0.00446

Gnomad4 FIN exome AF: 0.000243

Gnomad4 NFE exome AF: 0.000399

Gnomad4 OTH exome AF: 0.00267

GnomAD4 genome AF: 0.00536 AC: 816 AN: 152338 Hom.: 3 Cov.: 32 AF XY: 0.00548 AC XY: 408 AN XY: 74496

Gnomad4 AFR AF: 0.0158

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00713

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000603

Gnomad4 OTH AF: 0.00756

Alfa AF: 0.00179 Hom.: 0

Bravo AF: 0.00616

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0170 AC: 75

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.00352 AC: 428

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.000981

EpiControl AF: 0.000830

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.059
DANN	Benign	0.46
DEOGEN2	Benign	0.056	.;T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.49	T;T;.
MetaRNN	Benign	0.0025	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.89	.;N;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.67	N;N;N
REVEL	Benign	0.053
Sift	Benign	0.59	T;T;T
Sift4G	Benign	0.31	T;T;T
Polyphen		0.0020	.;B;.
Vest4		0.079
MVP		0.48
MPC		0.31
ClinPred		0.00026	T
GERP RS		-4.8
Varity_R		0.13
gMVP		0.24

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

Publications

LitVar

Other links and lift over

dbSNP: rs12721497; hg19: chr3-45943130; COSMIC: COSV62940244; COSMIC: COSV62940244;