19-8056476-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005624.4(CCL25):c.302A>T(p.His101Leu) 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 benign outcome for this variant. 14/21 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. H101R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CCL25 NM_005624.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.19

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06309199).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCL25	NM_005624.4	c.302A>T	p.His101Leu	missense_variant	4/6	ENST00000315626.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCL25	ENST00000315626.6	c.302A>T	p.His101Leu	missense_variant	4/6	2	NM_005624.4	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 41

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.72
Cadd	Benign	0.0080
Dann	Benign	0.26
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.0081	N
LIST_S2	Benign	0.18	T;T;T
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.063	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.46	N;N;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.20	T
PROVEAN	Uncertain	-3.1	D;D;.
REVEL	Benign	0.010
Sift	Benign	0.54	T;T;.
Sift4G	Benign	0.57	T;T;T
Polyphen		0.0	.;B;.
Vest4		0.17
MutPred		0.30		Loss of catalytic residue at K99 (P = 0.0757);Loss of catalytic residue at K99 (P = 0.0757);Loss of catalytic residue at K99 (P = 0.0757);
MVP		0.12
MPC		0.44
ClinPred		0.032	T
GERP RS		-3.0
Varity_R		0.055
gMVP		0.19

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

Publications

LitVar

Other links and lift over

dbSNP: rs2032887; hg19: chr19-8121360;