NM_014143.4:c.394+1999C>T

Variant names:

• chr9-5459419-C-T
• rs1411262
• NM_014143.4:c.394+1999C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014143.4(CD274):​c.394+1999C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.327 in 151,920 control chromosomes in the GnomAD database, including 8,793 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.33 (8793 hom., cov: 32)
• Consequence: CD274 NM_014143.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.355
• Publications: 21 publications found

Genes affected

CD274 (HGNC:17635): (CD274 molecule) This gene encodes an immune inhibitory receptor ligand that is expressed by hematopoietic and non-hematopoietic cells, such as T cells and B cells and various types of tumor cells. The encoded protein is a type I transmembrane protein that has immunoglobulin V-like and C-like domains. Interaction of this ligand with its receptor inhibits T-cell activation and cytokine production. During infection or inflammation of normal tissue, this interaction is important for preventing autoimmunity by maintaining homeostasis of the immune response. In tumor microenvironments, this interaction provides an immune escape for tumor cells through cytotoxic T-cell inactivation. Expression of this gene in tumor cells is considered to be prognostic in many types of human malignancies, including colon cancer and renal cell carcinoma. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2015]

CD274 Gene-Disease associations (from GenCC):

• neonatal diabetes mellitus

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000286162 (HGNC:56906):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.533 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD274	NM_014143.4	c.394+1999C>T		intron_variant	Intron 3 of 6	ENST00000381577.4	NP_054862.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD274	ENST00000381577.4	c.394+1999C>T		intron_variant	Intron 3 of 6	1	NM_014143.4	ENSP00000370989.3

Frequencies

GnomAD3 genomes AF: 0.327 AC: 49613 AN: 151802 Hom.: 8775 Cov.: 32

Gnomad AFR AF: 0.436

Gnomad AMI AF: 0.358

Gnomad AMR AF: 0.356

Gnomad ASJ AF: 0.213

Gnomad EAS AF: 0.549

Gnomad SAS AF: 0.250

Gnomad FIN AF: 0.260

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.260

Gnomad OTH AF: 0.287

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.327 AC: 49678 AN: 151920 Hom.: 8793 Cov.: 32 AF XY: 0.330 AC XY: 24489 AN XY: 74238

African (AFR) AF: 0.436 AC: 18039 AN: 41408

American (AMR) AF: 0.357 AC: 5441 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.213 AC: 740 AN: 3470

East Asian (EAS) AF: 0.550 AC: 2834 AN: 5152

South Asian (SAS) AF: 0.250 AC: 1201 AN: 4812

European-Finnish (FIN) AF: 0.260 AC: 2755 AN: 10582

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.260 AC: 17681 AN: 67942

Other (OTH) AF: 0.285 AC: 601 AN: 2108

Alfa AF: 0.284 Hom.: 20445

Bravo AF: 0.343

Asia WGS AF: 0.363 AC: 1261 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.6
DANN	Benign	0.47
PhyloP100		0.35
Mutation Taster		=100/0	polymorphism (auto)

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: rs1411262; hg19: chr9-5459419;