2-118970116-C-G

Position:

• chr2-118970116-C-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_006770.4(MARCO):​c.202C>G​(p.Leu68Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000801 in 1,613,786 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00064 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00082 (2 hom.)
• Consequence: MARCO NM_006770.4 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.465

Genes affected

MARCO (HGNC:6895): (macrophage receptor with collagenous structure) The protein encoded by this gene is a member of the class A scavenger receptor family and is part of the innate antimicrobial immune system. The protein may bind both Gram-negative and Gram-positive bacteria via an extracellular, C-terminal, scavenger receptor cysteine-rich (SRCR) domain. In addition to short cytoplasmic and transmembrane domains, there is an extracellular spacer domain and a long, extracellular collagenous domain. The protein may form a trimeric molecule by the association of the collagenous domains of three identical polypeptide chains. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09755772).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MARCO	NM_006770.4	c.202C>G	p.Leu68Val	missense_variant, splice_region_variant	3/17	ENST00000327097.5	NP_006761.1
MARCO	XM_011512082.3	c.202C>G	p.Leu68Val	missense_variant, splice_region_variant	3/17		XP_011510384.1
MARCO	XM_017005171.3	c.202C>G	p.Leu68Val	missense_variant, splice_region_variant	3/9		XP_016860660.1
MARCO	XM_011512083.4	c.98-4217C>G		intron_variant			XP_011510385.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MARCO	ENST00000327097.5	c.202C>G	p.Leu68Val	missense_variant, splice_region_variant	3/17	1	NM_006770.4	ENSP00000318916.4
MARCO	ENST00000412481	c.-33C>G		5_prime_UTR_premature_start_codon_gain_variant	4/4	4		ENSP00000409192.1
MARCO	ENST00000412481.1	c.-33C>G		splice_region_variant	4/4	4		ENSP00000409192.1
MARCO	ENST00000412481	c.-33C>G		5_prime_UTR_variant	4/4	4		ENSP00000409192.1

Frequencies

GnomAD3 genomes AF: 0.000637 AC: 97 AN: 152206 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000823

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000508 AC: 127 AN: 250168 Hom.: 1 AF XY: 0.000546 AC XY: 74 AN XY: 135486

Gnomad AFR exome AF: 0.000127

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000621

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000725

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000818 AC: 1195 AN: 1461462 Hom.: 2 Cov.: 32 AF XY: 0.000818 AC XY: 595 AN XY: 727052

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000693

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000603

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000944

Gnomad4 OTH exome AF: 0.000911

GnomAD4 genome AF: 0.000637 AC: 97 AN: 152324 Hom.: 1 Cov.: 32 AF XY: 0.000577 AC XY: 43 AN XY: 74480

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000823

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000717 Hom.: 0

Bravo AF: 0.000578

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000511 AC: 62

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.00101

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

Jan 30, 2024

The c.202C>G (p.L68V) alteration is located in exon 3 (coding exon 3) of the MARCO gene. This alteration results from a C to G substitution at nucleotide position 202, causing the leucine (L) at amino acid position 68 to be replaced by a valine (V). 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	0.16
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	15
DANN	Benign	0.92
DEOGEN2	Benign	0.084	T
Eigen	Benign	0.00012
Eigen_PC	Benign	-0.044
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.66	T
M_CAP	Uncertain	0.089	D
MetaRNN	Benign	0.098	T
MetaSVM	Uncertain	0.060	D
MutationAssessor	Benign	1.8	L
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.35
Sift	Benign	0.21	T
Sift4G	Uncertain	0.017	D
Polyphen		0.96	P
Vest4		0.24
MVP		0.87
MPC		0.29
ClinPred		0.10	T
GERP RS		3.5
Varity_R		0.12
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs144080988; hg19: chr2-119727692;