rs1143683

Positions:

• chr16-31325567-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000632.4(ITGAM):​c.2573C>T​(p.Ala858Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.154 in 1,613,704 control chromosomes in the GnomAD database, including 20,815 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.16 (2230 hom., cov: 31)
  • Exomes 𝑓: 0.15 (18585 hom.)
• Consequence: ITGAM NM_000632.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0680

Genes affected

ITGAM (HGNC:6149): (integrin subunit alpha M) This gene encodes the integrin alpha M chain. Integrins are heterodimeric integral membrane proteins composed of an alpha chain and a beta chain. This I-domain containing alpha integrin combines with the beta 2 chain (ITGB2) to form a leukocyte-specific integrin referred to as macrophage receptor 1 ('Mac-1'), or inactivated-C3b (iC3b) receptor 3 ('CR3'). The alpha M beta 2 integrin is important in the adherence of neutrophils and monocytes to stimulated endothelium, and also in the phagocytosis of complement coated particles. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006079823).
• BP6: Variant 16-31325567-C-T is Benign according to our data. Variant chr16-31325567-C-T is described in ClinVar as [Benign]. Clinvar id is 1164968.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-31325567-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.237 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITGAM	NM_000632.4	c.2573C>T	p.Ala858Val	missense_variant	21/30	ENST00000544665.9	NP_000623.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITGAM	ENST00000544665.9	c.2573C>T	p.Ala858Val	missense_variant	21/30	1	NM_000632.4	ENSP00000441691	P4
ITGAM	ENST00000648685.1	c.2576C>T	p.Ala859Val	missense_variant	21/30			ENSP00000496959	A1
ITGAM	ENST00000561838.1	n.389C>T		non_coding_transcript_exon_variant	4/5	4

Frequencies

GnomAD3 genomes AF: 0.164 AC: 24910 AN: 151958 Hom.: 2230 Cov.: 31

Gnomad AFR AF: 0.185

Gnomad AMI AF: 0.191

Gnomad AMR AF: 0.148

Gnomad ASJ AF: 0.251

Gnomad EAS AF: 0.0145

Gnomad SAS AF: 0.249

Gnomad FIN AF: 0.128

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.160

Gnomad OTH AF: 0.186

GnomAD3 exomes AF: 0.157 AC: 39170 AN: 249184 Hom.: 3762 AF XY: 0.165 AC XY: 22289 AN XY: 135180

Gnomad AFR exome AF: 0.191

Gnomad AMR exome AF: 0.103

Gnomad ASJ exome AF: 0.241

Gnomad EAS exome AF: 0.0117

Gnomad SAS exome AF: 0.252

Gnomad FIN exome AF: 0.126

Gnomad NFE exome AF: 0.164

Gnomad OTH exome AF: 0.171

GnomAD4 exome AF: 0.153 AC: 223600 AN: 1461626 Hom.: 18585 Cov.: 35 AF XY: 0.157 AC XY: 114124 AN XY: 727098

Gnomad4 AFR exome AF: 0.190

Gnomad4 AMR exome AF: 0.109

Gnomad4 ASJ exome AF: 0.244

Gnomad4 EAS exome AF: 0.00499

Gnomad4 SAS exome AF: 0.251

Gnomad4 FIN exome AF: 0.126

Gnomad4 NFE exome AF: 0.149

Gnomad4 OTH exome AF: 0.166

GnomAD4 genome AF: 0.164 AC: 24925 AN: 152078 Hom.: 2230 Cov.: 31 AF XY: 0.163 AC XY: 12150 AN XY: 74340

Gnomad4 AFR AF: 0.185

Gnomad4 AMR AF: 0.148

Gnomad4 ASJ AF: 0.251

Gnomad4 EAS AF: 0.0141

Gnomad4 SAS AF: 0.249

Gnomad4 FIN AF: 0.128

Gnomad4 NFE AF: 0.160

Gnomad4 OTH AF: 0.187

Alfa AF: 0.166 Hom.: 5804

Bravo AF: 0.163

TwinsUK AF: 0.147 AC: 544

ALSPAC AF: 0.142 AC: 548

ESP6500AA AF: 0.177 AC: 716

ESP6500EA AF: 0.159 AC: 1324

ExAC AF: 0.163 AC: 19651

Asia WGS AF: 0.137 AC: 476 AN: 3478

EpiCase AF: 0.174

EpiControl AF: 0.177

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

ITGAM-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 12, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	2.8
DANN	Benign	0.72
DEOGEN2	Benign	0.028	.;.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.42	.;T;T
MetaRNN	Benign	0.0061	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	.;.;L
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.3	.;N;N
REVEL	Benign	0.043
Sift	Benign	0.14	.;T;T
Sift4G	Benign	0.55	.;T;T
Polyphen		0.0010	.;.;B
Vest4		0.016, 0.020
MPC		0.30
ClinPred		0.0013	T
GERP RS		-1.5
Varity_R		0.025
gMVP		0.21

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: rs1143683; hg19: chr16-31336888; COSMIC: COSV54933565; COSMIC: COSV54933565;