9-5465732-G-A

Variant names:

• chr9-5465732-G-A
• rs2297137
• NM_014143.4:c.790+126G>A

Variant summary

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

The NM_014143.4(CD274):​c.790+126G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.221 in 604,260 control chromosomes in the GnomAD database, including 17,279 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 0.18 (3458 hom., cov: 32)
  • Exomes 𝑓: 0.23 (13821 hom.)
• Consequence: CD274 NM_014143.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.239
• Publications: 19 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=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.467 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014143.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD274	NM_014143.4	MANE Select	c.790+126G>A		intron	N/A	NP_054862.1
	CD274	NM_001267706.2		c.448+126G>A		intron	N/A	NP_001254635.1
	CD274	NR_052005.2		n.686+193G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD274	ENST00000381577.4	TSL:1 MANE Select	c.790+126G>A		intron	N/A	ENSP00000370989.3
	CD274	ENST00000498261.1	TSL:1	n.617+193G>A		intron	N/A
	CD274	ENST00000381573.8	TSL:5	c.448+126G>A		intron	N/A	ENSP00000370985.4

Frequencies

GnomAD3 genomes AF: 0.185 AC: 28122 AN: 152096 Hom.: 3455 Cov.: 32

Gnomad AFR AF: 0.0434

Gnomad AMI AF: 0.325

Gnomad AMR AF: 0.270

Gnomad ASJ AF: 0.179

Gnomad EAS AF: 0.482

Gnomad SAS AF: 0.180

Gnomad FIN AF: 0.230

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.222

Gnomad OTH AF: 0.170

GnomAD4 exome AF: 0.234 AC: 105664 AN: 452046 Hom.: 13821 Cov.: 5 AF XY: 0.232 AC XY: 55747 AN XY: 240124

African (AFR) AF: 0.0436 AC: 551 AN: 12632

American (AMR) AF: 0.298 AC: 6180 AN: 20738

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 2647 AN: 14074

East Asian (EAS) AF: 0.475 AC: 14260 AN: 30034

South Asian (SAS) AF: 0.177 AC: 7953 AN: 44882

European-Finnish (FIN) AF: 0.234 AC: 7948 AN: 34000

Middle Eastern (MID) AF: 0.170 AC: 534 AN: 3146

European-Non Finnish (NFE) AF: 0.225 AC: 60109 AN: 266832

Other (OTH) AF: 0.213 AC: 5482 AN: 25708

GnomAD4 genome AF: 0.185 AC: 28121 AN: 152214 Hom.: 3458 Cov.: 32 AF XY: 0.190 AC XY: 14137 AN XY: 74402

African (AFR) AF: 0.0432 AC: 1797 AN: 41568

American (AMR) AF: 0.270 AC: 4122 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.179 AC: 622 AN: 3470

East Asian (EAS) AF: 0.483 AC: 2493 AN: 5166

South Asian (SAS) AF: 0.180 AC: 867 AN: 4828

European-Finnish (FIN) AF: 0.230 AC: 2432 AN: 10578

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.222 AC: 15085 AN: 68012

Other (OTH) AF: 0.169 AC: 358 AN: 2114

Alfa AF: 0.206 Hom.: 3330

Bravo AF: 0.182

Asia WGS AF: 0.271 AC: 940 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.4
DANN	Benign	0.64
PhyloP100		0.24
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: rs2297137; hg19: chr9-5465732; COSMIC: COSV67501962;