ZAP70 p.Asp327Glu

Variant names:

• chr2-97734611-C-A
• NM_001079.4:c.981C>A
• ZAP70 p.Asp327Glu

Your query was ambiguous. Multiple possible variants found:

• chr2-97734611-C-A
• chr2-97734611-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001079.4(ZAP70):​c.981C>A​(p.Asp327Glu) 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. 17/22 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D327N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ZAP70 NM_001079.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0150
• Publications: 0 publications found

Genes affected

ZAP70 (HGNC:12858): (zeta chain of T cell receptor associated protein kinase 70) This gene encodes an enzyme belonging to the protein tyrosine kinase family, and it plays a role in T-cell development and lymphocyte activation. This enzyme, which is phosphorylated on tyrosine residues upon T-cell antigen receptor (TCR) stimulation, functions in the initial step of TCR-mediated signal transduction in combination with the Src family kinases, Lck and Fyn. This enzyme is also essential for thymocyte development. Mutations in this gene cause selective T-cell defect, a severe combined immunodeficiency disease characterized by a selective absence of CD8-positive T-cells. Two transcript variants that encode different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ZAP70 Gene-Disease associations (from GenCC):

• combined immunodeficiency due to ZAP70 deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08307624).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001079.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZAP70	NM_001079.4	MANE Select	c.981C>A	p.Asp327Glu	missense	Exon 9 of 14	NP_001070.2
	ZAP70	NM_001378594.1		c.981C>A	p.Asp327Glu	missense	Exon 8 of 13	NP_001365523.1	P43403-1
	ZAP70	NM_207519.2		c.60C>A	p.Asp20Glu	missense	Exon 1 of 6	NP_997402.1	P43403-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZAP70	ENST00000264972.10	TSL:1 MANE Select	c.981C>A	p.Asp327Glu	missense	Exon 9 of 14	ENSP00000264972.5	P43403-1
	ZAP70	ENST00000451498.2	TSL:1	c.60C>A	p.Asp20Glu	missense	Exon 1 of 6	ENSP00000400475.2	P43403-2
	ZAP70	ENST00000463643.5	TSL:1	n.842C>A		non_coding_transcript_exon	Exon 8 of 13

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	20
DANN	Benign	0.51
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.0092	T
MetaRNN	Benign	0.083	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.015
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.10
Sift	Benign	0.90	T
Sift4G	Benign	1.0	T
PromoterAI		-0.044	Neutral
Varity_R		0.11
gMVP		0.58
Mutation Taster		=74/26	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr2-98351074;