NM_004383.3:c.-66+4413G>A

Variant names:

• chr15-74787133-G-A
• rs34933034
• NM_004383.3:c.-66+4413G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_004383.3(CSK):​c.-66+4413G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 152,238 control chromosomes in the GnomAD database, including 1,237 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.11 (1237 hom., cov: 31)
• Consequence: CSK NM_004383.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.67
• Publications: 27 publications found

Genes affected

CSK (HGNC:2444): (C-terminal Src kinase) The protein encoded by this gene is involved in multiple pathways, including the regulation of Src family kinases. It plays an important role in T-cell activation through its association with the protein encoded by the protein tyrosine phosphatase, non-receptor type 22 (PTPN22) gene. This protein also phosphorylates C-terminal tyrosine residues on multiple substrates, including the protein encoded by the SRC proto-oncogene, non-receptor tyrosine kinase gene. Phosphorylation suppresses the kinase activity of the Src family tyrosine kinases. An intronic polymorphism (rs34933034) in this gene has been found to affect B-cell activation and is associated with systemic lupus erythematosus (SLE). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2017]

ENSG00000299491 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSK	NM_004383.3	c.-66+4413G>A		intron_variant	Intron 1 of 12	ENST00000220003.14	NP_004374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSK	ENST00000220003.14	c.-66+4413G>A		intron_variant	Intron 1 of 12	1	NM_004383.3	ENSP00000220003.9

Frequencies

GnomAD3 genomes AF: 0.115 AC: 17432 AN: 152120 Hom.: 1236 Cov.: 31

Gnomad AFR AF: 0.0359

Gnomad AMI AF: 0.258

Gnomad AMR AF: 0.127

Gnomad ASJ AF: 0.154

Gnomad EAS AF: 0.0306

Gnomad SAS AF: 0.157

Gnomad FIN AF: 0.123

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.128

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.115 AC: 17438 AN: 152238 Hom.: 1237 Cov.: 31 AF XY: 0.115 AC XY: 8580 AN XY: 74434

African (AFR) AF: 0.0358 AC: 1488 AN: 41556

American (AMR) AF: 0.127 AC: 1937 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.154 AC: 533 AN: 3470

East Asian (EAS) AF: 0.0307 AC: 159 AN: 5178

South Asian (SAS) AF: 0.158 AC: 762 AN: 4834

European-Finnish (FIN) AF: 0.123 AC: 1306 AN: 10612

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.158 AC: 10712 AN: 67996

Other (OTH) AF: 0.128 AC: 270 AN: 2108

Alfa AF: 0.0533 Hom.: 88

Bravo AF: 0.108

Asia WGS AF: 0.0810 AC: 281 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	19
DANN	Benign	0.86
PhyloP100		2.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs34933034; hg19: chr15-75079474;