rs2277998

Positions:

• chr19-7766742-G-A

Variant summary

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

The NM_014257.5(CLEC4M):​c.871G>A​(p.Asp291Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.283 in 1,614,058 control chromosomes in the GnomAD database, including 67,733 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.23 (5214 hom., cov: 32)
  • Exomes 𝑓: 0.29 (62519 hom.)
• Consequence: CLEC4M NM_014257.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.25

Genes affected

CLEC4M (HGNC:13523): (C-type lectin domain family 4 member M) This gene encodes a C-type lectin that functions in cell adhesion and pathogen recognition. This receptor recognizes a wide range of evolutionarily divergent pathogens with a large impact on public health, including tuberculosis mycobacteria, and viruses including Ebola, hepatitis C, HIV-1, influenza A, West Nile virus and the SARS-CoV acute respiratory syndrome coronavirus. The protein is organized into four distinct domains: a C-terminal carbohydrate recognition domain, a flexible tandem-repeat neck domain of variable length, a transmembrane region and an N-terminal cytoplasmic domain involved in internalization. This gene is closely related in terms of both sequence and function to a neighboring gene, CD209 (Gene ID: 30835), also known as DC-SIGN. The two genes differ in viral recognition and expression patterns, with this gene showing high expression in endothelial cells of the liver, lymph node and placenta. Polymorphisms in the tandem repeat neck domain are associated with resistance to SARS infection. [provided by RefSeq, May 2020]

CLEC4M (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009361863).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.319 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLEC4M	NM_014257.5	c.871G>A	p.Asp291Asn	missense_variant	5/7	ENST00000327325.10	NP_055072.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLEC4M	ENST00000327325.10	c.871G>A	p.Asp291Asn	missense_variant	5/7	1	NM_014257.5	ENSP00000316228.4

Frequencies

GnomAD3 genomes AF: 0.234 AC: 35648 AN: 152080 Hom.: 5205 Cov.: 32

Gnomad AFR AF: 0.0634

Gnomad AMI AF: 0.515

Gnomad AMR AF: 0.326

Gnomad ASJ AF: 0.216

Gnomad EAS AF: 0.152

Gnomad SAS AF: 0.205

Gnomad FIN AF: 0.308

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.311

Gnomad OTH AF: 0.252

GnomAD3 exomes AF: 0.269 AC: 67727 AN: 251452 Hom.: 10036 AF XY: 0.271 AC XY: 36875 AN XY: 135904

Gnomad AFR exome AF: 0.0543

Gnomad AMR exome AF: 0.324

Gnomad ASJ exome AF: 0.199

Gnomad EAS exome AF: 0.150

Gnomad SAS exome AF: 0.213

Gnomad FIN exome AF: 0.302

Gnomad NFE exome AF: 0.317

Gnomad OTH exome AF: 0.289

GnomAD4 exome AF: 0.288 AC: 421035 AN: 1461860 Hom.: 62519 Cov.: 63 AF XY: 0.287 AC XY: 209058 AN XY: 727238

Gnomad4 AFR exome AF: 0.0480

Gnomad4 AMR exome AF: 0.327

Gnomad4 ASJ exome AF: 0.199

Gnomad4 EAS exome AF: 0.156

Gnomad4 SAS exome AF: 0.212

Gnomad4 FIN exome AF: 0.299

Gnomad4 NFE exome AF: 0.307

Gnomad4 OTH exome AF: 0.264

GnomAD4 genome AF: 0.234 AC: 35662 AN: 152198 Hom.: 5214 Cov.: 32 AF XY: 0.234 AC XY: 17440 AN XY: 74398

Gnomad4 AFR AF: 0.0632

Gnomad4 AMR AF: 0.327

Gnomad4 ASJ AF: 0.216

Gnomad4 EAS AF: 0.153

Gnomad4 SAS AF: 0.205

Gnomad4 FIN AF: 0.308

Gnomad4 NFE AF: 0.311

Gnomad4 OTH AF: 0.250

Alfa AF: 0.289 Hom.: 8231

Bravo AF: 0.230

TwinsUK AF: 0.310 AC: 1151

ALSPAC AF: 0.291 AC: 1122

ESP6500AA AF: 0.0685 AC: 302

ESP6500EA AF: 0.314 AC: 2704

ExAC AF: 0.265 AC: 32184

Asia WGS AF: 0.173 AC: 603 AN: 3478

EpiCase AF: 0.313

EpiControl AF: 0.323

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.0080
DANN	Benign	0.71
DEOGEN2	Benign	0.031	.;.;T;.;T;.;.;.;.;.
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.0017	N
LIST_S2	Benign	0.69	T;T;T;T;T;T;T;T;T;T
MetaRNN	Benign	0.0094	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	.;.;.;.;L;.;.;.;.;.
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-2.7	D;.;D;D;D;.;.;.;.;.
REVEL	Benign	0.023
Sift	Benign	0.19	T;.;T;T;T;.;.;.;.;.
Sift4G	Benign	0.27	T;T;T;T;T;T;T;T;T;T
Polyphen		0.0030, 0.0090, 0.029, 0.10, 0.0060, 0.010, 0.075	.;B;B;B;B;B;.;.;B;B
Vest4		0.090
MPC		0.24
ClinPred		0.0064	T
GERP RS		-5.1
Varity_R		0.12
gMVP		0.24

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: rs2277998; hg19: chr19-7831628; COSMIC: COSV50219193;