7-3301728-C-A

Variant names:

• chr7-3301728-C-A
• rs868254792
• NM_152744.4:c.142C>A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_152744.4(SDK1):​c.142C>A​(p.Pro48Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00505 in 977,352 control chromosomes in the GnomAD database, including 195 homozygotes. 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: 𝑓 0.022 (130 hom., cov: 29)
  • Exomes 𝑓: 0.0020 (65 hom.)
• Consequence: SDK1 NM_152744.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.58

Genes affected

SDK1 (HGNC:19307): (sidekick cell adhesion molecule 1) The protein encoded by this gene is a member of the immunoglobulin superfamily. The protein contains six immunoglobulin-like domains and thirteen fibronectin type III domains. Fibronectin type III domains are present in both extracellular and intracellular proteins and tandem repeats are known to contain binding sites for DNA, heparin and the cell surface. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2016]

SDK1-AS1 (HGNC:40883): (SDK1 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029640496).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0735 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDK1	NM_152744.4	c.142C>A	p.Pro48Thr	missense_variant	Exon 1 of 45	ENST00000404826.7	NP_689957.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDK1	ENST00000404826.7	c.142C>A	p.Pro48Thr	missense_variant	Exon 1 of 45	1	NM_152744.4	ENSP00000385899.2
SDK1	ENST00000389531.7	c.142C>A	p.Pro48Thr	missense_variant	Exon 1 of 44	5		ENSP00000374182.3
SDK1-AS1	ENST00000437354.1	n.224+501G>T		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes AF: 0.0224 AC: 3258 AN: 145166 Hom.: 130 Cov.: 29

Gnomad AFR AF: 0.0758

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00803

Gnomad ASJ AF: 0.00148

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000418

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00671

Gnomad NFE AF: 0.000352

Gnomad OTH AF: 0.0185

GnomAD4 exome AF: 0.00201 AC: 1674 AN: 832150 Hom.: 65 Cov.: 28 AF XY: 0.00189 AC XY: 727 AN XY: 384350

Gnomad4 AFR exome AF: 0.0886

Gnomad4 AMR exome AF: 0.00900

Gnomad4 ASJ exome AF: 0.00136

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000120

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000185

Gnomad4 OTH exome AF: 0.00407

GnomAD4 genome AF: 0.0225 AC: 3262 AN: 145202 Hom.: 130 Cov.: 29 AF XY: 0.0216 AC XY: 1523 AN XY: 70590

Gnomad4 AFR AF: 0.0757

Gnomad4 AMR AF: 0.00802

Gnomad4 ASJ AF: 0.00148

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000421

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000352

Gnomad4 OTH AF: 0.0183

Alfa AF: 0.00118 Hom.: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 09, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.142C>A (p.P48T) alteration is located in exon 1 (coding exon 1) of the SDK1 gene. This alteration results from a C to A substitution at nucleotide position 142, causing the proline (P) at amino acid position 48 to be replaced by a threonine (T). 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	0.071
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	2.7
DANN	Benign	0.54
DEOGEN2	Benign	0.025	T;T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.37	T;T;T
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.0030	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.;.
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.0	N;N;.
REVEL	Benign	0.014
Sift	Benign	0.37	T;T;.
Polyphen		0.0010	B;.;.
Vest4		0.11
MutPred		0.27		Gain of phosphorylation at P48 (P = 0.0017);Gain of phosphorylation at P48 (P = 0.0017);Gain of phosphorylation at P48 (P = 0.0017);
MVP		0.27
MPC		0.27
ClinPred		0.031	T
GERP RS		-0.35
Varity_R		0.030
gMVP		0.21

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

LitVar

Other links and lift over

dbSNP: rs868254792; hg19: chr7-3341360; COSMIC: COSV67367033;