9-5462876-C-G

Position:

• chr9-5462876-C-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The ENST00000381577.4(CD274):​c.437C>G​(p.Pro146Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00406 in 1,613,860 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P146T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0035 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (15 hom.)
• Consequence: CD274 ENST00000381577.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.835

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0062650144).
• BP6: Variant 9-5462876-C-G is Benign according to our data. Variant chr9-5462876-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 2659049.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CD274	NM_014143.4	c.437C>G	p.Pro146Arg	missense_variant	4/7	ENST00000381577.4	NP_054862.1
LOC124902114	XR_007061406.1	n.256-3689G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CD274	ENST00000381577.4	c.437C>G	p.Pro146Arg	missense_variant	4/7	1	NM_014143.4	ENSP00000370989	P1
	ENST00000661858.1	n.277-3689G>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00355 AC: 540 AN: 152160 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.00589

Gnomad ASJ AF: 0.0167

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00462

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00393 AC: 988 AN: 251104 Hom.: 1 AF XY: 0.00393 AC XY: 534 AN XY: 135706

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.00420

Gnomad ASJ exome AF: 0.0165

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00185

Gnomad NFE exome AF: 0.00512

Gnomad OTH exome AF: 0.00637

GnomAD4 exome AF: 0.00412 AC: 6017 AN: 1461582 Hom.: 15 Cov.: 31 AF XY: 0.00408 AC XY: 2964 AN XY: 727084

Gnomad4 AFR exome AF: 0.000658

Gnomad4 AMR exome AF: 0.00474

Gnomad4 ASJ exome AF: 0.0163

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000186

Gnomad4 FIN exome AF: 0.00217

Gnomad4 NFE exome AF: 0.00445

Gnomad4 OTH exome AF: 0.00442

GnomAD4 genome AF: 0.00355 AC: 540 AN: 152278 Hom.: 5 Cov.: 32 AF XY: 0.00324 AC XY: 241 AN XY: 74448

Gnomad4 AFR AF: 0.000553

Gnomad4 AMR AF: 0.00588

Gnomad4 ASJ AF: 0.0167

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.00462

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00521 Hom.: 1

Bravo AF: 0.00375

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00512 AC: 44

ExAC AF: 0.00367 AC: 446

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2022

CD274: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.56	.;D
Eigen	Benign	0.042
Eigen_PC	Benign	-0.029
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.76	T;T
M_CAP	Uncertain	0.093	D
MetaRNN	Benign	0.0063	T;T
MetaSVM	Benign	-0.53	T
MutationAssessor	Pathogenic	3.1	.;M
MutationTaster	Benign	0.95	D;D
PrimateAI	Benign	0.36	T
PROVEAN	Pathogenic	-4.9	D;D
REVEL	Benign	0.12
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		0.81	.;P
Vest4		0.14
MVP		0.49
MPC		1.2
ClinPred		0.10	T
GERP RS		4.0
Varity_R		0.37
gMVP		0.34

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

LitVar

Other links and lift over

dbSNP: rs17718883; hg19: chr9-5462876; COSMIC: COSV67502072; COSMIC: COSV67502072;