16-31278075-T-C

Variant names:

• chr16-31278075-T-C
• rs1143680
• NM_000632.4:c.1322T>C

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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
• Publications: 20 publications found

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]

ITGAM Gene-Disease associations (from GenCC):

• systemic lupus erythematosus

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000632.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGAM	NM_000632.4	MANE Select	c.1322T>C	p.Met441Thr	missense	Exon 12 of 30	NP_000623.2
	ITGAM	NM_001145808.2		c.1322T>C	p.Met441Thr	missense	Exon 12 of 30	NP_001139280.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGAM	ENST00000544665.9	TSL:1 MANE Select	c.1322T>C	p.Met441Thr	missense	Exon 12 of 30	ENSP00000441691.3
	ITGAM	ENST00000567031.1	TSL:1	c.310+1026T>C		intron	N/A	ENSP00000454568.1
	ITGAM	ENST00000648685.1		c.1322T>C	p.Met441Thr	missense	Exon 12 of 30	ENSP00000496959.1

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

GnomAD2 exomes AF: 0.107 AC: 25496 AN: 238718 AF XY: 0.105

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 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

African (AFR) AF: 0.190 AC: 6357 AN: 33382

American (AMR) AF: 0.0640 AC: 2802 AN: 43752

Ashkenazi Jewish (ASJ) AF: 0.0668 AC: 1732 AN: 25940

East Asian (EAS) AF: 0.000809 AC: 32 AN: 39540

South Asian (SAS) AF: 0.0472 AC: 4016 AN: 85060

European-Finnish (FIN) AF: 0.129 AC: 6837 AN: 53024

Middle Eastern (MID) AF: 0.0772 AC: 445 AN: 5762

European-Non Finnish (NFE) AF: 0.156 AC: 173532 AN: 1109120

Other (OTH) AF: 0.130 AC: 7828 AN: 60194

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

African (AFR) AF: 0.186 AC: 7732 AN: 41490

American (AMR) AF: 0.0951 AC: 1452 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.0672 AC: 233 AN: 3466

East Asian (EAS) AF: 0.00194 AC: 10 AN: 5162

South Asian (SAS) AF: 0.0417 AC: 201 AN: 4824

European-Finnish (FIN) AF: 0.131 AC: 1390 AN: 10582

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.152 AC: 10317 AN: 68002

Other (OTH) AF: 0.114 AC: 241 AN: 2108

Alfa AF: 0.137 Hom.: 4796

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

ITGAM-related disorder Benign:1

Oct 24, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 v4.9

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
MetaRNN	Benign	0.0062	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-1.3	N
PhyloP100		-1.6
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.82	N
REVEL	Benign	0.011
Sift	Benign	0.76	T
Sift4G	Benign	0.65	T
Polyphen		0.0	B
Vest4		0.010
MPC		0.33
ClinPred		0.000059	T
GERP RS		-0.078
Varity_R		0.048
gMVP		0.21
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1143680; hg19: chr16-31289396; COSMIC: COSV54937225; COSMIC: COSV54937225;