19-8056190-A-G

Variant names:

• chr19-8056190-A-G
• rs199918432
• NM_005624.4:c.112A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_005624.4(CCL25):​c.112A>G​(p.Ile38Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000919 in 1,556,716 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/23 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. I38T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000034 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000098 (1 hom.)
• Consequence: CCL25 NM_005624.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.812

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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0704132).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCL25	NM_005624.4	c.112A>G	p.Ile38Val	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.112A>G	p.Ile38Val	missense_variant	Exon 3 of 6	2	NM_005624.4	ENSP00000324756.6

Frequencies

GnomAD3 genomes AF: 0.0000337 AC: 5 AN: 148564 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000739

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000194 AC: 4 AN: 206466 AF XY: 0.0000271

Gnomad AFR exome AF: 0.00

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: 0.0000417

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000980 AC: 138 AN: 1408152 Hom.: 1 Cov.: 32 AF XY: 0.0000849 AC XY: 59 AN XY: 694968

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 31886

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 36684

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 22482

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39166

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 77076

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 51546

Gnomad4 NFE exome AF: 0.000125 AC: 136 AN: 1085882

Gnomad4 Remaining exome AF: 0.0000345 AC: 2 AN: 57922

GnomAD4 genome AF: 0.0000337 AC: 5 AN: 148564 Hom.: 0 Cov.: 31 AF XY: 0.0000416 AC XY: 3 AN XY: 72056

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000739 AC: 0.0000739076 AN: 0.0000739076

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.0000764 Hom.: 0

Bravo AF: 0.0000604

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000237 AC: 2

ExAC AF: 0.0000414 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 10, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.112A>G (p.I38V) alteration is located in exon 3 (coding exon 2) of the CCL25 gene. This alteration results from a A to G substitution at nucleotide position 112, causing the isoleucine (I) at amino acid position 38 to be replaced by a valine (V). 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	0.074
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.0020
DANN	Benign	0.26
DEOGEN2	Benign	0.070	.;T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0040	N
LIST_S2	Benign	0.32	T;T;T
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.070	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;L;.
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.10	N;N;N
REVEL	Benign	0.021
Sift	Benign	0.49	T;T;T
Sift4G	Benign	0.80	T;T;T
Polyphen		0.077, 0.048	.;B;B
Vest4		0.043
MVP		0.13
MPC		0.31
ClinPred		0.039	T
GERP RS		-7.3
Varity_R		0.016
gMVP		0.44
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs199918432; hg19: chr19-8121074;