chr17-48345997-A-T

Position:

• chr17-48345997-A-T

Variant summary

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

The NM_003726.4(SKAP1):​c.188T>A​(p.Ile63Asn) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SKAP1 NM_003726.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.244

Genes affected

SKAP1 (HGNC:15605): (src kinase associated phosphoprotein 1) This gene encodes a T cell adaptor protein, a class of intracellular molecules with modular domains capable of recruiting additional proteins but that exhibit no intrinsic enzymatic activity. The encoded protein contains a unique N-terminal region followed by a PH domain and C-terminal SH3 domain. Along with the adhesion and degranulation-promoting adaptor protein, the encoded protein plays a critical role in inside-out signaling by coupling T-cell antigen receptor stimulation to the activation of integrins. [provided by RefSeq, Jul 2008]

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=0.023533046).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SKAP1	NM_003726.4	c.188T>A	p.Ile63Asn	missense_variant	4/13	ENST00000336915.11	NP_003717.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SKAP1	ENST00000336915.11	c.188T>A	p.Ile63Asn	missense_variant	4/13	1	NM_003726.4	ENSP00000338171	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

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

Dec 22, 2023

The c.188T>A (p.I63N) alteration is located in exon 4 (coding exon 4) of the SKAP1 gene. This alteration results from a T to A substitution at nucleotide position 188, causing the isoleucine (I) at amino acid position 63 to be replaced by an asparagine (N). 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	0.069
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	9.8
DANN	Benign	0.91
DEOGEN2	Benign	0.076	T;T
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.097	N
LIST_S2	Benign	0.48	.;T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.024	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.55	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.60	N;.
REVEL	Benign	0.040
Sift	Benign	0.49	T;.
Sift4G	Benign	0.36	T;T
Polyphen		0.023	B;B
Vest4		0.19
MutPred		0.36		Loss of catalytic residue at I63 (P = 0.0069);Loss of catalytic residue at I63 (P = 0.0069);
MVP		0.10
MPC		0.36
ClinPred		0.067	T
GERP RS		0.057
Varity_R		0.067
gMVP		0.22

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: chr17-46423359;