17-48137250-C-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.1066G>A(p.Val356Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,960 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SKAP1 NM_003726.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.19

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=0.01780495).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SKAP1	NM_003726.4	c.1066G>A	p.Val356Met	missense_variant	12/13	ENST00000336915.11
SKAP1	NM_001075099.2	c.1063G>A	p.Val355Met	missense_variant	12/13
SKAP1	XM_005257755.5	c.1012G>A	p.Val338Met	missense_variant	11/12
SKAP1	XM_017025258.2	c.799G>A	p.Val267Met	missense_variant	9/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SKAP1	ENST00000336915.11	c.1066G>A	p.Val356Met	missense_variant	12/13	1	NM_003726.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460960 Hom.: 0 Cov.: 29 AF XY: 0.00000275 AC XY: 2 AN XY: 726834

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.0000166

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

Jul 14, 2022

The c.1066G>A (p.V356M) alteration is located in exon 12 (coding exon 12) of the SKAP1 gene. This alteration results from a G to A substitution at nucleotide position 1066, causing the valine (V) at amino acid position 356 to be replaced by a methionine (M). 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	0.081
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.72
Cadd	Benign	0.67
Dann	Benign	0.56
DEOGEN2	Benign	0.091	T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.020	N
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.018	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.29	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.42	N;.
REVEL	Benign	0.0020
Sift	Benign	0.18	T;.
Sift4G	Benign	0.22	T;T
Polyphen		0.0010	B;B
Vest4		0.076
MutPred		0.19		Gain of disorder (P = 0.0989);Gain of disorder (P = 0.0989);
MVP		0.17
MPC		0.20
ClinPred		0.041	T
GERP RS		-8.4
Varity_R		0.024
gMVP		0.25

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: chr17-46214612;