Genetic Variant CD247:p.Gln70Pro (chr1-167439354-T-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM2PM5BP4_Moderate

The NM_198053.3(CD247):c.209A>C(p.Gln70Pro) 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. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q70Y) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

CD247
NM_198053.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.867

Publications

3 publications found

Variant links:

Genes affected

CD247 (HGNC:1677): (CD247 molecule) The protein encoded by this gene is T-cell receptor zeta, which together with T-cell receptor alpha/beta and gamma/delta heterodimers, and with CD3-gamma, -delta and -epsilon, forms the T-cell receptor-CD3 complex. The zeta chain plays an important role in coupling antigen recognition to several intracellular signal-transduction pathways. Low expression of the antigen results in impaired immune response. Two alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

CD247 Gene-Disease associations (from GenCC):

immunodeficiency 25
Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
T-B+ severe combined immunodeficiency due to CD3delta/CD3epsilon/CD3zeta
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CD247 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-167439353-CTG-ATA is described in ClinVar as Pathogenic. ClinVar VariationId is 12752.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.20266539).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198053.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CD247	NM_198053.3	MANE Select	c.209A>C	p.Gln70Pro	missense	Exon 3 of 8	NP_932170.1
CD247	NM_001378515.1		c.302A>C	p.Gln101Pro	missense	Exon 4 of 9	NP_001365444.1
CD247	NM_001378516.1		c.302A>C	p.Gln101Pro	missense	Exon 4 of 9	NP_001365445.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CD247	ENST00000362089.10	TSL:1 MANE Select	c.209A>C	p.Gln70Pro	missense	Exon 3 of 8	ENSP00000354782.5
CD247	ENST00000392122.4	TSL:1	c.209A>C	p.Gln70Pro	missense	Exon 3 of 8	ENSP00000375969.3
CD247	ENST00000470379.2	TSL:1	c.-77A>C		5_prime_UTR	Exon 1 of 6	ENSP00000514807.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251442

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.31

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.097

LIST_S2

Benign

0.66

M_CAP

Benign

0.019

MetaRNN

Benign

0.20

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.4

PhyloP100

0.87

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-4.0

REVEL

Benign

0.037

Sift

Benign

0.15

Sift4G

Benign

0.24

Polyphen

0.0040

Vest4

0.42

MutPred

0.61

Gain of glycosylation at Q70 (P = 0.0224)

MVP

0.42

MPC

0.19

ClinPred

0.55

GERP RS

0.16

Varity_R

0.69

gMVP

0.39

Mutation Taster

=37/63

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over