4-10501313-T-C

Variant names:

• chr4-10501313-T-C
• rs2903960
• NM_052964.4:c.1083A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_052964.4(CLNK):​c.1083A>G​(p.Ile361Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I361I) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CLNK NM_052964.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.610
• Publications: 14 publications found

Genes affected

CLNK (HGNC:17438): (cytokine dependent hematopoietic cell linker) MIST is a member of the SLP76 family of adaptors (see LCP2, MIM 601603; BLNK, MIM 604515). MIST plays a role in the regulation of immunoreceptor signaling, including PLC-gamma (PLCG1; MIM 172420)-mediated B cell antigen receptor (BCR) signaling and FC-epsilon R1 (see FCER1A, MIM 147140)-mediated mast cell degranulation (Cao et al., 1999 [PubMed 10562326]; Goitsuka et al., 2000, 2001 [PubMed 10744659] [PubMed 11463797]).[supplied by OMIM, Mar 2008]

ENSG00000287154 (HGNC:58732):

LOC105374482 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052964.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLNK	NM_052964.4	MANE Select	c.1083A>G	p.Ile361Met	missense	Exon 18 of 19	NP_443196.2	Q7Z7G1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLNK	ENST00000226951.11	TSL:1 MANE Select	c.1083A>G	p.Ile361Met	missense	Exon 18 of 19	ENSP00000226951.6	Q7Z7G1-1
	CLNK	ENST00000515667.5	TSL:3	c.297A>G	p.Ile99Met	missense	Exon 4 of 5	ENSP00000427256.1	D6RJB9
	ENSG00000287154	ENST00000663264.1		n.97-28821T>C		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.87e-7 AC: 1 AN: 1455132 Hom.: 0 Cov.: 45 AF XY: 0.00000138 AC XY: 1 AN XY: 723818

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33010

American (AMR) AF: 0.00 AC: 0 AN: 42898

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25980

East Asian (EAS) AF: 0.00 AC: 0 AN: 39428

South Asian (SAS) AF: 0.00 AC: 0 AN: 84880

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53346

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109724

Other (OTH) AF: 0.00 AC: 0 AN: 60124

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		0.61
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.69
MutPred		0.65		Gain of MoRF binding (P = 0.0957)
MVP		0.33
MPC		0.035
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.51
gMVP		0.50
Mutation Taster		=76/24	polymorphism

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: rs2903960; hg19: chr4-10502937;