19-8056191-T-C

Variant names:

• chr19-8056191-T-C
• rs769482360
• NM_005624.4:c.113T>C

Variant summary

Our verdict is Uncertain significance. The variant received 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. 15/23 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

Our verdict: Uncertain_significance. The variant received 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 rank	MANE	Protein	UniProt
CCL25	NM_005624.4	c.113T>C	p.Ile38Thr	missense_variant	Exon 3 of 6	ENST00000315626.6	NP_005615.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCL25	ENST00000315626.6	c.113T>C	p.Ile38Thr	missense_variant	Exon 3 of 6	2	NM_005624.4	ENSP00000324756.6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000484 AC: 1 AN: 206670 AF XY: 0.00

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 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 AC: 0 AN: 31778

Gnomad4 AMR exome AF: 0.0000546 AC: 2 AN: 36648

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 22412

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 38910

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 77120

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 51394

Gnomad4 NFE exome AF: 0.00000461 AC: 5 AN: 1084200

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 57824

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

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

Sep 22, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
DEOGEN2	Benign	0.32	.;T;.
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;.
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
Mutation Taster		=98/2	polymorphism

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;