3-111542260-A-T

Position:

• chr3-111542260-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The NM_005816.5(CD96):​c.12A>T​(p.Lys4Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CD96 NM_005816.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.920

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]

CD96 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-111542260-A-T is Pathogenic according to our data. Variant chr3-111542260-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 3362818.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.25999707). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CD96	NM_005816.5	c.12A>T	p.Lys4Asn	missense_variant	1/14	ENST00000352690.9	NP_005807.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CD96	ENST00000352690.9	c.12A>T	p.Lys4Asn	missense_variant	1/14	1	NM_005816.5	ENSP00000342040.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

C syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The observed missense c.12A>T (p.Lys4Asn) variant in CD96 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Lys4Asn variant is absent in gnomAD Exomes. This variant has not been submitted to the ClinVar database. Computational evidence (Polyphen - Probably Damaging, SIFT - Damaging and MutationTaster - Polymorphism) predicts conflicting evidence on protein structure and function for this variant. The reference amino acid of p.Ser440Pro in PORCN is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ser at position 440 is changed to a Pro changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.054	.;.;T;.
Eigen	Benign	0.12
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.70	.;T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.26	T;T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.0	.;M;M;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.3	.;N;N;N
REVEL	Benign	0.12
Sift	Uncertain	0.024	.;D;D;D
Sift4G	Benign	0.17	.;T;T;T
Polyphen		0.99, 0.98, 0.91	.;D;D;P
Vest4		0.14, 0.12, 0.50
MutPred		0.29		Loss of methylation at K4 (P = 0.0012);Loss of methylation at K4 (P = 0.0012);Loss of methylation at K4 (P = 0.0012);Loss of methylation at K4 (P = 0.0012);
MVP		0.72
MPC		0.063
ClinPred		0.65	D
GERP RS		1.9
Varity_R		0.13
gMVP		0.31

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-111261107;