rs11861251

Positions:

• chr16-31278075-T-C
• chr16-31278075-T-A

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.1322T>C​(p.Met441Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.14 in 1,607,880 control chromosomes in the GnomAD database, including 17,232 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 0.14 (1704 hom., cov: 32)
  • Exomes 𝑓: 0.14 (15528 hom.)
• Consequence: ITGAM NM_000632.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.55

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=0.006170988).
• BP6: Variant 16-31278075-T-C is Benign according to our data. Variant chr16-31278075-T-C is described in ClinVar as [Benign]. Clinvar id is 1168376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.183 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGAM	NM_000632.4	c.1322T>C	p.Met441Thr	missense_variant	12/30	ENST00000544665.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGAM	ENST00000544665.9	c.1322T>C	p.Met441Thr	missense_variant	12/30	1	NM_000632.4	P4
ITGAM	ENST00000567031.1	c.312+1026T>C		intron_variant		1
ITGAM	ENST00000648685.1	c.1322T>C	p.Met441Thr	missense_variant	12/30			A1

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21690 AN: 151988 Hom.: 1705 Cov.: 32

Gnomad AFR AF: 0.187

Gnomad AMI AF: 0.0844

Gnomad AMR AF: 0.0953

Gnomad ASJ AF: 0.0672

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.0414

Gnomad FIN AF: 0.131

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.152

Gnomad OTH AF: 0.116

GnomAD3 exomes AF: 0.107 AC: 25496 AN: 238718 Hom.: 1665 AF XY: 0.105 AC XY: 13592 AN XY: 129346

Gnomad AFR exome AF: 0.186

Gnomad AMR exome AF: 0.0597

Gnomad ASJ exome AF: 0.0663

Gnomad EAS exome AF: 0.00177

Gnomad SAS exome AF: 0.0447

Gnomad FIN exome AF: 0.129

Gnomad NFE exome AF: 0.144

Gnomad OTH exome AF: 0.112

GnomAD4 exome AF: 0.140 AC: 203581 AN: 1455774 Hom.: 15528 Cov.: 32 AF XY: 0.137 AC XY: 99287 AN XY: 723502

Gnomad4 AFR exome AF: 0.190

Gnomad4 AMR exome AF: 0.0640

Gnomad4 ASJ exome AF: 0.0668

Gnomad4 EAS exome AF: 0.000809

Gnomad4 SAS exome AF: 0.0472

Gnomad4 FIN exome AF: 0.129

Gnomad4 NFE exome AF: 0.156

Gnomad4 OTH exome AF: 0.130

GnomAD4 genome AF: 0.143 AC: 21694 AN: 152106 Hom.: 1704 Cov.: 32 AF XY: 0.139 AC XY: 10365 AN XY: 74338

Gnomad4 AFR AF: 0.186

Gnomad4 AMR AF: 0.0951

Gnomad4 ASJ AF: 0.0672

Gnomad4 EAS AF: 0.00194

Gnomad4 SAS AF: 0.0417

Gnomad4 FIN AF: 0.131

Gnomad4 NFE AF: 0.152

Gnomad4 OTH AF: 0.114

Alfa AF: 0.133 Hom.: 3053

Bravo AF: 0.140

TwinsUK AF: 0.165 AC: 613

ALSPAC AF: 0.160 AC: 617

ESP6500AA AF: 0.176 AC: 728

ESP6500EA AF: 0.151 AC: 1270

ExAC AF: 0.108 AC: 13059

Asia WGS AF: 0.0620 AC: 215 AN: 3478

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	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

ITGAM-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 24, 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	0.065
BayesDel_addAF	Benign	-0.87	T
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.27
DANN	Benign	0.20
DEOGEN2	Benign	0.015	.;.;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0025	N
LIST_S2	Benign	0.26	.;T;T
MetaRNN	Benign	0.0062	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-1.3	N;N;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.82	.;N;N
REVEL	Benign	0.011
Sift	Benign	0.76	.;T;T
Sift4G	Benign	0.65	.;T;T
Polyphen		0.0	.;.;B
Vest4		0.010, 0.012
MPC		0.33
ClinPred		0.000059	T
GERP RS		-0.078
Varity_R		0.048
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: rs1143680; hg19: chr16-31289396; COSMIC: COSV54937225; COSMIC: COSV54937225;