10-44377772-A-G

Variant summary

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

The ENST00000395794.2(CXCL12):c.400T>C(p.Trp134Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000553 in 1,446,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: CXCL12 ENST00000395794.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.46

Genes affected

CXCL12 (HGNC:10672): (C-X-C motif chemokine ligand 12) This antimicrobial gene encodes a stromal cell-derived alpha chemokine member of the intercrine family. The encoded protein functions as the ligand for the G-protein coupled receptor, chemokine (C-X-C motif) receptor 4, and plays a role in many diverse cellular functions, including embryogenesis, immune surveillance, inflammation response, tissue homeostasis, and tumor growth and metastasis. Mutations in this gene are associated with resistance to human immunodeficiency virus type 1 infections. Multiple transcript variants encoding different isoforms have been found for this gene. [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=0.12558052).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CXCL12	NM_199168.4	c.*861T>C		3_prime_UTR_variant	3/3	ENST00000343575.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CXCL12	ENST00000343575.11	c.*861T>C		3_prime_UTR_variant	3/3	1	NM_199168.4	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000216 AC: 5 AN: 231274 Hom.: 0 AF XY: 0.0000157 AC XY: 2 AN XY: 127682

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 SAS exome AF: 0.0000991

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000185

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000553 AC: 8 AN: 1446006 Hom.: 0 Cov.: 32 AF XY: 0.00000417 AC XY: 3 AN XY: 719706

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000868 Hom.: 0

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

Dec 01, 2022

The c.400T>C (p.W134R) alteration is located in exon 4 (coding exon 4) of the CXCL12 gene. This alteration results from a T to C substitution at nucleotide position 400, causing the tryptophan (W) at amino acid position 134 to be replaced by an arginine (R). 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
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	8.7
Dann	Benign	0.61
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.21	T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.10
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.38
MutPred		0.11		Loss of catalytic residue at P137 (P = 0.0267);
MVP		0.21
MPC		0.49
ClinPred		0.12	T
GERP RS		-1.5
gMVP		0.29

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: rs1040912964; hg19: chr10-44873220;