rs1143679

Positions:

• chr16-31265490-G-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.230G>A​(p.Arg77His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 1,592,706 control chromosomes in the GnomAD database, including 8,785 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R77C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.11 (979 hom., cov: 31)
  • Exomes 𝑓: 0.10 (7806 hom.)
• Consequence: ITGAM NM_000632.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.52

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=0.0012870133).
• BP6: Variant 16-31265490-G-A is Benign according to our data. Variant chr16-31265490-G-A is described in ClinVar as [Benign]. Clinvar id is 1164965.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGAM	NM_000632.4	c.230G>A	p.Arg77His	missense_variant	3/30	ENST00000544665.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGAM	ENST00000544665.9	c.230G>A	p.Arg77His	missense_variant	3/30	1	NM_000632.4	P4
ITGAM	ENST00000648685.1	c.230G>A	p.Arg77His	missense_variant	3/30			A1

Frequencies

GnomAD3 genomes AF: 0.108 AC: 16424 AN: 152038 Hom.: 974 Cov.: 31

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.191

Gnomad AMR AF: 0.102

Gnomad ASJ AF: 0.152

Gnomad EAS AF: 0.00638

Gnomad SAS AF: 0.0664

Gnomad FIN AF: 0.118

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.139

GnomAD3 exomes AF: 0.0967 AC: 21083 AN: 218036 Hom.: 1170 AF XY: 0.0975 AC XY: 11570 AN XY: 118716

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.0749

Gnomad ASJ exome AF: 0.137

Gnomad EAS exome AF: 0.00454

Gnomad SAS exome AF: 0.0686

Gnomad FIN exome AF: 0.116

Gnomad NFE exome AF: 0.117

Gnomad OTH exome AF: 0.114

GnomAD4 exome AF: 0.101 AC: 144937 AN: 1440550 Hom.: 7806 Cov.: 29 AF XY: 0.101 AC XY: 71936 AN XY: 715476

Gnomad4 AFR exome AF: 0.108

Gnomad4 AMR exome AF: 0.0794

Gnomad4 ASJ exome AF: 0.140

Gnomad4 EAS exome AF: 0.00188

Gnomad4 SAS exome AF: 0.0718

Gnomad4 FIN exome AF: 0.115

Gnomad4 NFE exome AF: 0.105

Gnomad4 OTH exome AF: 0.108

GnomAD4 genome AF: 0.108 AC: 16456 AN: 152156 Hom.: 979 Cov.: 31 AF XY: 0.108 AC XY: 8042 AN XY: 74402

Gnomad4 AFR AF: 0.106

Gnomad4 AMR AF: 0.102

Gnomad4 ASJ AF: 0.152

Gnomad4 EAS AF: 0.00620

Gnomad4 SAS AF: 0.0675

Gnomad4 FIN AF: 0.118

Gnomad4 NFE AF: 0.116

Gnomad4 OTH AF: 0.138

Alfa AF: 0.117 Hom.: 2212

Bravo AF: 0.106

TwinsUK AF: 0.102 AC: 380

ALSPAC AF: 0.0978 AC: 377

ESP6500AA AF: 0.0912 AC: 375

ESP6500EA AF: 0.113 AC: 958

ExAC AF: 0.0922 AC: 11141

Asia WGS AF: 0.0460 AC: 159 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

ITGAM-related disorder Benign:1

Benign, criteria provided, single submitter

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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.11
DANN	Benign	0.90
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.022	N
MetaRNN	Benign	0.0013	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.060	N;N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.21	T
Polyphen		0.0020	.;.;B
Vest4		0.059, 0.12
MPC		0.36
ClinPred		0.0045	T
GERP RS		-9.3
Varity_R		0.020
gMVP		0.36

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: rs1143679; hg19: chr16-31276811; COSMIC: COSV54938377;