12-8138162-A-T

Position:

• chr12-8138162-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_016184.4(CLEC4A):​c.589A>T​(p.Ser197Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CLEC4A NM_016184.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.47

Genes affected

CLEC4A (HGNC:13257): (C-type lectin domain family 4 member A) This gene encodes a member of the C-type lectin/C-type lectin-like domain (CTL/CTLD) superfamily. Members of this family share a common protein fold and have diverse functions, such as cell adhesion, cell-cell signalling, glycoprotein turnover, and roles in inflammation and immune response. The encoded type 2 transmembrane protein may play a role in inflammatory and immune response. Multiple transcript variants encoding distinct isoforms have been identified for this gene. This gene is closely linked to other CTL/CTLD superfamily members on chromosome 12p13 in the natural killer gene complex region. [provided by RefSeq, Jul 2008]

ENSG00000284393 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity CLC4A_HUMAN
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLEC4A	NM_016184.4	c.589A>T	p.Ser197Cys	missense_variant	6/6	ENST00000229332.12	NP_057268.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLEC4A	ENST00000229332.12	c.589A>T	p.Ser197Cys	missense_variant	6/6	1	NM_016184.4	ENSP00000229332.5
ENSG00000284393	ENST00000402465.8	n.22A>T		non_coding_transcript_exon_variant	1/5	2		ENSP00000384896.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

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

May 15, 2023

The c.589A>T (p.S197C) alteration is located in exon 6 (coding exon 6) of the CLEC4A gene. This alteration results from a A to T substitution at nucleotide position 589, causing the serine (S) at amino acid position 197 to be replaced by a cysteine (C). 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	Pathogenic	0.69
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.055	T;.;.;.
Eigen	Uncertain	0.39
Eigen_PC	Benign	0.22
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.70	T;T;T;T
M_CAP	Benign	0.0055	T
MetaRNN	Uncertain	0.44	T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.8	M;.;.;.
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-4.2	D;D;D;D
REVEL	Benign	0.27
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.25
MutPred		0.56		Gain of catalytic residue at P196 (P = 0.0123);.;.;.;
MVP		0.59
MPC		0.30
ClinPred		0.93	D
GERP RS		4.0
Varity_R		0.47
gMVP		0.56

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: rs1043734406; hg19: chr12-8290758;