17-48363802-A-C

Position:

• chr17-48363802-A-C

Variant summary

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

The NM_003726.4(SKAP1):​c.165T>G​(p.Asp55Glu) 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: -0.437

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=0.044982463).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SKAP1	NM_003726.4	c.165T>G	p.Asp55Glu	missense_variant	3/13	ENST00000336915.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SKAP1	ENST00000336915.11	c.165T>G	p.Asp55Glu	missense_variant	3/13	1	NM_003726.4	P1
SKAP1	ENST00000584924.5	c.165T>G	p.Asp55Glu	missense_variant	3/12	2		P1
SKAP1	ENST00000584709.5	c.165T>G	p.Asp55Glu	missense_variant, NMD_transcript_variant	3/14	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

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 14, 2023

The c.165T>G (p.D55E) alteration is located in exon 3 (coding exon 3) of the SKAP1 gene. This alteration results from a T to G substitution at nucleotide position 165, causing the aspartic acid (D) at amino acid position 55 to be replaced by a glutamic acid (E). 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	0.14
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	5.2
DANN	Benign	0.61
DEOGEN2	Benign	0.072	T;T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.22	N
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.045	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;L
MutationTaster	Benign	0.96	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.22	N;.
REVEL	Benign	0.082
Sift	Benign	1.0	T;.
Sift4G	Benign	1.0	T;T
Polyphen		0.0020	B;B
Vest4		0.13
MutPred		0.38		Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);
MVP		0.25
MPC		0.18
ClinPred		0.047	T
GERP RS		-2.0
Varity_R		0.018
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr17-46441164;