10-44373096-T-C

Variant names:

• chr10-44373096-T-C
• rs140248633
• ENST00000374429:c.*232A>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_001277990.2(CXCL12):​c.110-6A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00294 in 1,536,422 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (7 hom.)
• Consequence: CXCL12 NM_001277990.2 splice_region, intron
• Scores: Splicing: ADA: 0.00003135
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.397

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: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 10-44373096-T-C is Benign according to our data. Variant chr10-44373096-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3037442.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAdExome4 at 7 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CXCL12	NM_000609.7	c.*232A>G		3_prime_UTR_variant	Exon 4 of 4		NP_000600.1
CXCL12	NM_001277990.2	c.110-6A>G		splice_region_variant, intron_variant	Intron 2 of 2		NP_001264919.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CXCL12	ENST00000374429	c.*232A>G		3_prime_UTR_variant	Exon 4 of 4	1		ENSP00000363551.2
CXCL12	ENST00000395793.7	c.110-6A>G		splice_region_variant, intron_variant	Intron 2 of 2	5		ENSP00000379139.3

Frequencies

GnomAD3 genomes AF: 0.00235 AC: 358 AN: 152250 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000868

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00394

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00222 AC: 310 AN: 139700 AF XY: 0.00242

Gnomad AFR exome AF: 0.000427

Gnomad AMR exome AF: 0.00144

Gnomad ASJ exome AF: 0.000604

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000616

Gnomad NFE exome AF: 0.00410

Gnomad OTH exome AF: 0.00337

GnomAD4 exome AF: 0.00301 AC: 4161 AN: 1384054 Hom.: 7 Cov.: 34 AF XY: 0.00302 AC XY: 2065 AN XY: 682800

Gnomad4 AFR exome AF: 0.000349 AC: 11 AN: 31498

Gnomad4 AMR exome AF: 0.00167 AC: 59 AN: 35412

Gnomad4 ASJ exome AF: 0.000678 AC: 17 AN: 25082

Gnomad4 EAS exome AF: 0.0000280 AC: 1 AN: 35706

Gnomad4 SAS exome AF: 0.000835 AC: 66 AN: 79010

Gnomad4 FIN exome AF: 0.000587 AC: 21 AN: 35770

Gnomad4 NFE exome AF: 0.00355 AC: 3823 AN: 1078078

Gnomad4 Remaining exome AF: 0.00246 AC: 142 AN: 57814

GnomAD4 genome AF: 0.00235 AC: 358 AN: 152368 Hom.: 1 Cov.: 33 AF XY: 0.00203 AC XY: 151 AN XY: 74508

Gnomad4 AFR AF: 0.000866 AC: 0.000865634 AN: 0.000865634

Gnomad4 AMR AF: 0.00170 AC: 0.00169824 AN: 0.00169824

Gnomad4 ASJ AF: 0.00230 AC: 0.00230415 AN: 0.00230415

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000414 AC: 0.000413907 AN: 0.000413907

Gnomad4 FIN AF: 0.000941 AC: 0.000941088 AN: 0.000941088

Gnomad4 NFE AF: 0.00394 AC: 0.00393932 AN: 0.00393932

Gnomad4 OTH AF: 0.00378 AC: 0.00378072 AN: 0.00378072

Alfa AF: 0.00277 Hom.: 1

Bravo AF: 0.00232

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

CXCL12-related disorder Benign:1

Feb 19, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	9.1
DANN	Benign	0.75
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000031
dbscSNV1_RF	Benign	0.012

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

Publications

LitVar

Other links and lift over

dbSNP: rs140248633; hg19: chr10-44868544;