5-135578780-C-G

Variant summary

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

The ENST00000337225.5(CXCL14):c.35G>C(p.Ser12Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000707 in 1,541,036 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00042 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: CXCL14 ENST00000337225.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.61

Genes affected

CXCL14 (HGNC:10640): (C-X-C motif chemokine ligand 14) This antimicrobial gene belongs to the cytokine gene family which encode secreted proteins involved in immunoregulatory and inflammatory processes. The protein encoded by this gene is structurally related to the CXC (Cys-X-Cys) subfamily of cytokines. Members of this subfamily are characterized by two cysteines separated by a single amino acid. This cytokine displays chemotactic activity for monocytes but not for lymphocytes, dendritic cells, neutrophils or macrophages. It has been implicated that this cytokine is involved in the homeostasis of monocyte-derived macrophages rather than in inflammation. [provided by RefSeq, Sep 2014]

(HGNC:):

SLC25A48 (HGNC:30451): (solute carrier family 25 member 48) Predicted to enable acyl carnitine transmembrane transporter activity. Predicted to be involved in acyl carnitine transport and amino acid transport. Predicted to be located in mitochondrial inner membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

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=0.04737985).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CXCL14	NM_004887.5	c.-2G>C		5_prime_UTR_variant	1/4	ENST00000512158.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CXCL14	ENST00000512158.6	c.-2G>C		5_prime_UTR_variant	1/4	1	NM_004887.5	P1
	ENST00000698884.1	n.497-50457C>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000420 AC: 64 AN: 152248 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000894 AC: 12 AN: 134162 Hom.: 0 AF XY: 0.0000967 AC XY: 7 AN XY: 72426

Gnomad AFR exome AF: 0.00144

Gnomad AMR exome AF: 0.0000928

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: 0.0000324 AC: 45 AN: 1388670 Hom.: 0 Cov.: 31 AF XY: 0.0000438 AC XY: 30 AN XY: 685160

Gnomad4 AFR exome AF: 0.00123

Gnomad4 AMR exome AF: 0.0000613

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000521

GnomAD4 genome AF: 0.000420 AC: 64 AN: 152366 Hom.: 0 Cov.: 34 AF XY: 0.000362 AC XY: 27 AN XY: 74506

Gnomad4 AFR AF: 0.00147

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000849 Hom.: 0

Bravo AF: 0.000378

ExAC AF: 0.0000506 AC: 3

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

Jul 06, 2021

The c.35G>C (p.S12T) alteration is located in exon 1 (coding exon 1) of the CXCL14 gene. This alteration results from a G to C substitution at nucleotide position 35, causing the serine (S) at amino acid position 12 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	0.085
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	19
Dann	Uncertain	0.98
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.047	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	D;N
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.12
Sift	Benign	0.28	T
Sift4G	Benign	1.0	T
Polyphen		0.0020	B
Vest4		0.39
MVP		0.42
MPC		0.93
ClinPred		0.050	T
GERP RS		3.9
Varity_R		0.12
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs772253716; hg19: chr5-134914470;