10-44377786-G-A

Variant names:

• chr10-44377786-G-A
• rs188984713
• ENST00000395794.2:c.386C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001178134.2(CXCL12):​c.386C>T​(p.Pro129Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00015 in 1,598,256 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 0.00068 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000094 (0 hom.)
• Consequence: CXCL12 NM_001178134.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.691

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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014266521).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CXCL12	NM_199168.4	c.*847C>T		3_prime_UTR_variant	Exon 3 of 3	ENST00000343575.11	NP_954637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CXCL12	ENST00000343575	c.*847C>T		3_prime_UTR_variant	Exon 3 of 3	1	NM_199168.4	ENSP00000339913.6

Frequencies

GnomAD3 genomes AF: 0.000676 AC: 103 AN: 152262 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00224

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

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: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000186 AC: 43 AN: 230886 AF XY: 0.000157

Gnomad AFR exome AF: 0.00231

Gnomad AMR exome AF: 0.0000876

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000371

Gnomad OTH exome AF: 0.000513

GnomAD4 exome AF: 0.0000941 AC: 136 AN: 1445876 Hom.: 0 Cov.: 32 AF XY: 0.0000792 AC XY: 57 AN XY: 719614

Gnomad4 AFR exome AF: 0.00248 AC: 83 AN: 33470

Gnomad4 AMR exome AF: 0.000112 AC: 5 AN: 44706

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26126

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39690

Gnomad4 SAS exome AF: 0.0000697 AC: 6 AN: 86142

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 38006

Gnomad4 NFE exome AF: 0.0000189 AC: 21 AN: 1111734

Gnomad4 Remaining exome AF: 0.000299 AC: 18 AN: 60256

GnomAD4 genome AF: 0.000676 AC: 103 AN: 152380 Hom.: 0 Cov.: 33 AF XY: 0.000564 AC XY: 42 AN XY: 74514

Gnomad4 AFR AF: 0.00224 AC: 0.00223579 AN: 0.00223579

Gnomad4 AMR AF: 0.000457 AC: 0.000457218 AN: 0.000457218

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: 0.0000294 AC: 0.0000293945 AN: 0.0000293945

Gnomad4 OTH AF: 0.000473 AC: 0.00047259 AN: 0.00047259

Alfa AF: 0.00114 Hom.: 0

Bravo AF: 0.000763

ESP6500AA AF: 0.00171 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000166 AC: 19

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.386C>T (p.P129L) alteration is located in exon 4 (coding exon 4) of the CXCL12 gene. This alteration results from a C to T substitution at nucleotide position 386, causing the proline (P) at amino acid position 129 to be replaced by a leucine (L). 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	-0.52	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	12
DANN	Uncertain	0.99
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.96	T
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.031
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.25
MVP		0.57
MPC		0.38
ClinPred		0.083	T
GERP RS		1.2
gMVP		0.34
Mutation Taster		=97/3	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: rs188984713; hg19: chr10-44873234;