Genetic Variant CXCL12:c.267-65T>G (chr10-44373408-A-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000374429.6(CXCL12):c.267-65T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.855 in 1,449,630 control chromosomes in the GnomAD database, including 530,960 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.84 ( 53777 hom., cov: 34)

Exomes 𝑓: 0.86 ( 477183 hom. )

Consequence

CXCL12
ENST00000374429.6 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.497

Publications

6 publications found

Variant links:

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]

CXCL12 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 10-44373408-A-C is Benign according to our data. Variant chr10-44373408-A-C is described in ClinVar as Benign. ClinVar VariationId is 1280296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.902 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CXCL12	NM_001277990.2 link	c.110-318T>G		intron_variant	Intron 2 of 2		NP_001264919.1
CXCL12	NM_000609.7 link	c.267-65T>G		intron_variant	Intron 3 of 3		NP_000600.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CXCL12	ENST00000374429.6 link	c.267-65T>G		intron_variant	Intron 3 of 3	1		ENSP00000363551.2
CXCL12	ENST00000395793.7 link	c.110-318T>G		intron_variant	Intron 2 of 2	5		ENSP00000379139.3

Frequencies

GnomAD3 genomes

AF:

0.838

AC:

127537

AN:

152120

Hom.:

53730

Cov.:

show subpopulations

Gnomad AFR

AF:

0.741

Gnomad AMI

AF:

0.848

Gnomad AMR

AF:

0.914

Gnomad ASJ

AF:

0.850

Gnomad EAS

AF:

0.864

Gnomad SAS

AF:

0.850

Gnomad FIN

AF:

0.934

Gnomad MID

AF:

0.848

Gnomad NFE

AF:

0.861

Gnomad OTH

AF:

0.868

GnomAD4 exome

AF:

0.857

AC:

1111998

AN:

1297392

Hom.:

477183

AF XY:

0.857

AC XY:

557043

AN XY:

649856

show subpopulations

African (AFR)

AF:

0.739

AC:

22101

AN:

29898

American (AMR)

AF:

0.927

AC:

36920

AN:

39812

Ashkenazi Jewish (ASJ)

AF:

0.858

AC:

21105

AN:

24608

East Asian (EAS)

AF:

0.842

AC:

31359

AN:

37224

South Asian (SAS)

AF:

0.853

AC:

67027

AN:

78554

European-Finnish (FIN)

AF:

0.922

AC:

47265

AN:

51288

Middle Eastern (MID)

AF:

0.868

AC:

4769

AN:

5494

European-Non Finnish (NFE)

AF:

0.855

AC:

834327

AN:

975586

Other (OTH)

AF:

0.858

AC:

47125

AN:

54928

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

8303

16607

24910

33214

41517

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17868

35736

53604

71472

89340

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.838

AC:

127638

AN:

152238

Hom.:

53777

Cov.:

AF XY:

0.843

AC XY:

62768

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.742

AC:

30803

AN:

41530

American (AMR)

AF:

0.915

AC:

13998

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.850

AC:

2952

AN:

3472

East Asian (EAS)

AF:

0.864

AC:

4446

AN:

5148

South Asian (SAS)

AF:

0.849

AC:

4099

AN:

4828

European-Finnish (FIN)

AF:

0.934

AC:

9922

AN:

10624

Middle Eastern (MID)

AF:

0.857

AC:

252

AN:

294

European-Non Finnish (NFE)

AF:

0.861

AC:

58555

AN:

68010

Other (OTH)

AF:

0.869

AC:

1838

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1085

2169

3254

4338

5423

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

890

1780

2670

3560

4450

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.842

Hom.:

7408

Bravo

AF:

0.834

Asia WGS

AF:

0.836

AC:

2905

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Nov 11, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

1.5

(source)

DANN

Benign

0.49

PhyloP100

-0.50

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over