3-111545313-G-A

Variant names:

• chr3-111545313-G-A
• rs372870533
• NM_005816.5:c.329G>A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_005816.5(CD96):​c.329G>A​(p.Cys110Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000125 in 1,613,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: CD96 NM_005816.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.40

Genes affected

CD96 (HGNC:16892): (CD96 molecule) The protein encoded by this gene belongs to the immunoglobulin superfamily. It is a type I membrane protein. The protein may play a role in the adhesive interactions of activated T and NK cells during the late phase of the immune response. It may also function in antigen presentation. Alternative splicing generates multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.030688494).
• BP6: Variant 3-111545313-G-A is Benign according to our data. Variant chr3-111545313-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2654027.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAd4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD96	NM_005816.5	c.329G>A	p.Cys110Tyr	missense_variant	Exon 2 of 14	ENST00000352690.9	NP_005807.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD96	ENST00000352690.9	c.329G>A	p.Cys110Tyr	missense_variant	Exon 2 of 14	1	NM_005816.5	ENSP00000342040.3

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000720 AC: 18 AN: 250144 Hom.: 0 AF XY: 0.0000813 AC XY: 11 AN XY: 135320

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000711

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000122 AC: 179 AN: 1461794 Hom.: 0 Cov.: 32 AF XY: 0.000106 AC XY: 77 AN XY: 727190

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000150

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74350

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000851

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000847 Hom.: 0

Bravo AF: 0.000147

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Dec 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.329G>A (p.C110Y) alteration is located in exon 2 (coding exon 2) of the CD96 gene. This alteration results from a G to A substitution at nucleotide position 329, causing the cysteine (C) at amino acid position 110 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Jun 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CD96: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	16
DANN	Benign	0.81
DEOGEN2	Benign	0.027	.;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.49	T;T;T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.031	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.0	N;N;.
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.10	N;N;N
REVEL	Benign	0.10
Sift	Benign	0.085	T;D;D
Sift4G	Uncertain	0.0090	D;D;T
Polyphen		0.0	B;B;B
Vest4		0.12
MutPred		0.38		Gain of disorder (P = 0.1036);Gain of disorder (P = 0.1036);Gain of disorder (P = 0.1036);
MVP		0.095
MPC		0.021
ClinPred		0.060	T
GERP RS		5.2
Varity_R		0.15
gMVP		0.58

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: rs372870533; hg19: chr3-111264160;