19-8056191-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005624.4(CCL25):c.113T>C(p.Ile38Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000498 in 1,405,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I38V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000050 (0 hom.)
• Consequence: CCL25 NM_005624.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.95

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16984189).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCL25	NM_005624.4	c.113T>C	p.Ile38Thr	missense_variant	3/6	ENST00000315626.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCL25	ENST00000315626.6	c.113T>C	p.Ile38Thr	missense_variant	3/6	2	NM_005624.4	A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000484 AC: 1 AN: 206670 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 110650

Gnomad AFR exome AF: 0.0000666

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000498 AC: 7 AN: 1405782 Hom.: 0 Cov.: 32 AF XY: 0.00000432 AC XY: 3 AN XY: 693820

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000546

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000461

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000827 AC: 1

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

Sep 22, 2022

The c.113T>C (p.I38T) alteration is located in exon 3 (coding exon 2) of the CCL25 gene. This alteration results from a T to C substitution at nucleotide position 113, causing the isoleucine (I) at amino acid position 38 to be replaced by a threonine (T). 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	Benign	0.15
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	0.055
Dann	Benign	0.97
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0030	N
LIST_S2	Benign	0.44	T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Pathogenic	2.9	M;M;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-2.2	N;N;N
REVEL	Benign	0.071
Sift	Benign	0.12	T;T;D
Sift4G	Benign	0.085	T;T;T
Polyphen		0.17, 0.0090	.;B;B
Vest4		0.10
MutPred		0.60		Gain of glycosylation at I38 (P = 0.0373);Gain of glycosylation at I38 (P = 0.0373);Gain of glycosylation at I38 (P = 0.0373);
MVP		0.15
MPC		0.48
ClinPred		0.11	T
GERP RS		-7.3
Varity_R		0.046
gMVP		0.65

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

LitVar

Other links and lift over

dbSNP: rs769482360; hg19: chr19-8121075;