chr19-8056224-A-T

Position:

• chr19-8056224-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005624.4(CCL25):​c.146A>T​(p.Tyr49Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: CCL25 NM_005624.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.21

Genes affected

CCL25 (HGNC:10624): (C-C motif chemokine ligand 25) This antimicrobial gene belongs to the subfamily of small cytokine CC genes. Cytokines are a family of secreted proteins involved in immunoregulatory and inflammatory processes. The CC cytokines are proteins characterized by two adjacent cysteines. The cytokine encoded by this gene displays chemotactic activity for dendritic cells, thymocytes, and activated macrophages but is inactive on peripheral blood lymphocytes and neutrophils. The product of this gene binds to chemokine receptor CCR9. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.762

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCL25	NM_005624.4	c.146A>T	p.Tyr49Phe	missense_variant	3/6	ENST00000315626.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCL25	ENST00000315626.6	c.146A>T	p.Tyr49Phe	missense_variant	3/6	2	NM_005624.4	A1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 16, 2024

The c.146A>T (p.Y49F) alteration is located in exon 3 (coding exon 2) of the CCL25 gene. This alteration results from a A to T substitution at nucleotide position 146, causing the tyrosine (Y) at amino acid position 49 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.22	.;T;.
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.54	T;T;T
M_CAP	Benign	0.0068	T
MetaRNN	Pathogenic	0.76	D;D;D
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.0	M;M;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.3	D;D;D
REVEL	Benign	0.10
Sift	Benign	0.16	T;T;T
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.77, 0.36	.;P;B
Vest4		0.31
MutPred		0.80		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.46
MPC		0.86
ClinPred		0.64	D
GERP RS		3.0
Varity_R		0.23
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-8121108;