10-44377816-C-A

Variant names:

• chr10-44377816-C-A
• rs201470059
• ENST00000395794.2:c.356G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001178134.2(CXCL12):​c.356G>T​(p.Arg119Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,444,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R119Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CXCL12 NM_001178134.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.527
• Publications: 0 publications found

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: 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=0.19404185).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001178134.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CXCL12	NM_199168.4	MANE Select	c.*817G>T		3_prime_UTR	Exon 3 of 3	NP_954637.1	P48061-2
	CXCL12	NM_001178134.2		c.356G>T	p.Arg119Leu	missense	Exon 4 of 4	NP_001171605.1	P48061-4
	CXCL12	NM_001033886.2		c.266+821G>T		intron	N/A	NP_001029058.1	P48061-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CXCL12	ENST00000395794.2	TSL:1	c.356G>T	p.Arg119Leu	missense	Exon 4 of 4	ENSP00000379140.2	P48061-4
	CXCL12	ENST00000343575.11	TSL:1 MANE Select	c.*817G>T		3_prime_UTR	Exon 3 of 3	ENSP00000339913.6	P48061-2
	CXCL12	ENST00000374426.6	TSL:1	c.266+821G>T		intron	N/A	ENSP00000363548.2	P48061-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1444842 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 718994

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.00 AC: 0 AN: 44604

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39650

South Asian (SAS) AF: 0.00 AC: 0 AN: 85864

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37938

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5672

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111348

Other (OTH) AF: 0.00 AC: 0 AN: 60210

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	15
DANN	Uncertain	0.99
Eigen	Benign	0.0065
Eigen_PC	Benign	0.0012
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.53
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.041
Sift	Benign	0.084	T
Sift4G	Benign	0.27	T
Vest4		0.16
MutPred		0.27		Gain of helix (P = 0.0199)
MVP		0.66
MPC		0.080
ClinPred		0.68	D
GERP RS		3.1
gMVP		0.38
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs201470059; hg19: chr10-44873264; COSMIC: COSV59107147; COSMIC: COSV59107147;