Genetic Variant ENST00000395794.2:c.340G>C (chr10-44377832-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000395794.2(CXCL12):c.340G>C(p.Ala114Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000439 in 1,595,402 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000042 ( 0 hom. )

Consequence

CXCL12
ENST00000395794.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.16

Publications

0 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: 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=0.099159926).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000395794.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CXCL12	NM_199168.4	MANE Select	c.*801G>C		3_prime_UTR	Exon 3 of 3	NP_954637.1	P48061-2
CXCL12	NM_001178134.2		c.340G>C	p.Ala114Pro	missense	Exon 4 of 4	NP_001171605.1	P48061-4
CXCL12	NM_001033886.2		c.266+805G>C		intron	N/A	NP_001029058.1	P48061-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CXCL12	ENST00000395794.2	TSL:1	c.340G>C	p.Ala114Pro	missense	Exon 4 of 4	ENSP00000379140.2	P48061-4
CXCL12	ENST00000343575.11	TSL:1 MANE Select	c.*801G>C		3_prime_UTR	Exon 3 of 3	ENSP00000339913.6	P48061-2
CXCL12	ENST00000374426.6	TSL:1	c.266+805G>C		intron	N/A	ENSP00000363548.2	P48061-3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000447

AC:

AN:

223890

AF XY:

0.00000807

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000960

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000416

AC:

AN:

1443162

Hom.:

Cov.:

AF XY:

0.00000418

AC XY:

AN XY:

717982

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33410

American (AMR)

AF:

0.00

AC:

AN:

44336

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26058

East Asian (EAS)

AF:

0.00

AC:

AN:

39604

South Asian (SAS)

AF:

0.00

AC:

AN:

85548

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37820

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5626

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

1110636

Other (OTH)

AF:

0.0000166

AC:

AN:

60124

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.00000657

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74382

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41458

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68046

Other (OTH)

AF:

0.00

AC:

AN:

2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000874

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.77

CADD

Benign

1.2

(source)

DANN

Benign

0.96

Eigen

Benign

-0.95

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.34

M_CAP

Benign

0.0011

MetaRNN

Benign

0.099

MetaSVM

Benign

-1.0

PhyloP100

-1.2

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.25

REVEL

Benign

0.0060

Sift

Benign

0.088

Sift4G

Benign

0.17

Vest4

0.20

MutPred

0.24

Gain of catalytic residue at A114 (P = 0.0013)

MVP

0.22

MPC

0.082

ClinPred

0.071

GERP RS

-6.0

gMVP

0.28

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over