10-44373096-T-C

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

Verdict is Benign. Variant got -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

GnomAD3 exomes AF: 0.00222 AC: 310 AN: 139700 Hom.: 0 AF XY: 0.00242 AC XY: 182 AN XY: 75314

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 SAS exome AF: 0.000800

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

Gnomad4 AMR exome AF: 0.00167

Gnomad4 ASJ exome AF: 0.000678

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.000835

Gnomad4 FIN exome AF: 0.000587

Gnomad4 NFE exome AF: 0.00355

Gnomad4 OTH exome AF: 0.00246

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

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000941

Gnomad4 NFE AF: 0.00394

Gnomad4 OTH AF: 0.00378

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

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;