15-73702554-C-T

Position:

• chr15-73702554-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001024736.2(CD276):​c.379C>T​(p.Arg127Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000999 in 1,610,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (0 hom.)
• Consequence: CD276 NM_001024736.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.487

Genes affected

CD276 (HGNC:19137): (CD276 molecule) The protein encoded by this gene belongs to the immunoglobulin superfamily, and thought to participate in the regulation of T-cell-mediated immune response. Studies show that while the transcript of this gene is ubiquitously expressed in normal tissues and solid tumors, the protein is preferentially expressed only in tumor tissues. Additionally, it was observed that the 3' UTR of this transcript contains a target site for miR29 microRNA, and there is an inverse correlation between the expression of this protein and miR29 levels, suggesting regulation of expression of this gene product by miR29. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.022170216).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CD276	NM_001024736.2	c.379C>T	p.Arg127Trp	missense_variant	3/10	ENST00000318443.10	NP_001019907.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CD276	ENST00000318443.10	c.379C>T	p.Arg127Trp	missense_variant	3/10	2	NM_001024736.2	ENSP00000320084	P2

Frequencies

GnomAD3 genomes AF: 0.000618 AC: 94 AN: 152156 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00101

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000735 AC: 180 AN: 244746 Hom.: 0 AF XY: 0.000714 AC XY: 95 AN XY: 133130

Gnomad AFR exome AF: 0.000126

Gnomad AMR exome AF: 0.0000581

Gnomad ASJ exome AF: 0.00141

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000355

Gnomad NFE exome AF: 0.00137

Gnomad OTH exome AF: 0.000665

GnomAD4 exome AF: 0.00104 AC: 1516 AN: 1458838 Hom.: 0 Cov.: 34 AF XY: 0.00102 AC XY: 739 AN XY: 725780

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.0000896

Gnomad4 ASJ exome AF: 0.00115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000313

Gnomad4 NFE exome AF: 0.00128

Gnomad4 OTH exome AF: 0.000646

GnomAD4 genome AF: 0.000618 AC: 94 AN: 152156 Hom.: 0 Cov.: 33 AF XY: 0.000552 AC XY: 41 AN XY: 74324

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00101

Gnomad4 OTH AF: 0.000957

Alfa AF: 0.000897 Hom.: 0

Bravo AF: 0.000669

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000939 AC: 114

EpiCase AF: 0.00120

EpiControl AF: 0.00124

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 16, 2024

The c.379C>T (p.R127W) alteration is located in exon 3 (coding exon 2) of the CD276 gene. This alteration results from a C to T substitution at nucleotide position 379, causing the arginine (R) at amino acid position 127 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;T;.;T;.;.;T;T;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.41	N
LIST_S2	Uncertain	0.96	.;D;D;D;D;D;D;D;.
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.022	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.9	.;L;L;.;.;L;.;.;L
MutationTaster	Benign	0.92	D;D;D;N;N
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.6	D;N;D;N;D;N;D;D;D
REVEL	Benign	0.28
Sift	Uncertain	0.0020	D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.013	D;D;D;D;D;D;D;D;D
Polyphen		0.91, 0.99, 0.89	.;P;D;.;.;P;.;.;D
Vest4		0.42, 0.36, 0.41, 0.35
MVP		0.64
MPC		0.36
ClinPred		0.057	T
GERP RS		1.8
Varity_R		0.25
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs150953383; hg19: chr15-73994895;