19-7765658-C-A

Position:

• chr19-7765658-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014257.5(CLEC4M):​c.235C>A​(p.Leu79Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000966 in 1,614,258 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00047 (1 hom., cov: 31)
  • Exomes 𝑓: 0.000057 (0 hom.)
• Consequence: CLEC4M NM_014257.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.282

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.011660248).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLEC4M	NM_014257.5	c.235C>A	p.Leu79Ile	missense_variant	4/7	ENST00000327325.10	NP_055072.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLEC4M	ENST00000327325.10	c.235C>A	p.Leu79Ile	missense_variant	4/7	1	NM_014257.5	ENSP00000316228.4

Frequencies

GnomAD3 genomes AF: 0.000466 AC: 71 AN: 152256 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.0000875 AC: 22 AN: 251474 Hom.: 0 AF XY: 0.0000441 AC XY: 6 AN XY: 135906

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000575 AC: 84 AN: 1461884 Hom.: 0 Cov.: 32 AF XY: 0.0000509 AC XY: 37 AN XY: 727240

Gnomad4 AFR exome AF: 0.00131

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000473 AC: 72 AN: 152374 Hom.: 1 Cov.: 31 AF XY: 0.000443 AC XY: 33 AN XY: 74516

Gnomad4 AFR AF: 0.00149

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.0269 Hom.: 728

Bravo AF: 0.000408

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000132 AC: 16

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

Jun 18, 2021

The c.235C>A (p.L79I) alteration is located in exon 4 (coding exon 4) of the CLEC4M gene. This alteration results from a C to A substitution at nucleotide position 235, causing the leucine (L) at amino acid position 79 to be replaced by an isoleucine (I). 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	0.056
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0094	.;.;T;.;T;.;.;.;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0020	N
LIST_S2	Benign	0.081	T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.00098	T
MetaRNN	Benign	0.012	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.0	.;N;.;.;N;.;.;.;N;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.21	N;N;N;N;N;.;.;.;.;.
REVEL	Benign	0.0040
Sift	Benign	0.71	T;T;T;T;T;.;.;.;.;.
Sift4G	Benign	0.40	T;T;T;T;T;T;T;T;T;T
Polyphen		0.81, 0.0010, 0.0, 0.0070, 0.62	.;P;B;B;B;B;.;.;B;P
Vest4		0.10
MVP		0.061
MPC		0.27
ClinPred		0.0063	T
GERP RS		0.38
Varity_R		0.039
gMVP		0.016

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: rs147993793; hg19: chr19-7830544; COSMIC: COSV50219340; COSMIC: COSV50219340;