rs1143683

Variant names:

• chr16-31325567-C-T
• rs1143683
• NM_000632.4:c.2573C>T

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.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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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
• Publications: 49 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

ENSG00000289930 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 1164968.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
ITGAM	NM_000632.4	c.2573C>T	p.Ala858Val	missense_variant	Exon 21 of 30	ENST00000544665.9	NP_000623.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGAM	ENST00000544665.9	c.2573C>T	p.Ala858Val	missense_variant	Exon 21 of 30	1	NM_000632.4	ENSP00000441691.3
ITGAM	ENST00000648685.1	c.2576C>T	p.Ala859Val	missense_variant	Exon 21 of 30			ENSP00000496959.1
ITGAM	ENST00000561838.1	n.389C>T		non_coding_transcript_exon_variant	Exon 4 of 5	4
ENSG00000289930	ENST00000777754.1	n.*94G>A		downstream_gene_variant

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

GnomAD2 exomes AF: 0.157 AC: 39170 AN: 249184 AF XY: 0.165

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 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

African (AFR) AF: 0.190 AC: 6355 AN: 33474

American (AMR) AF: 0.109 AC: 4888 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.244 AC: 6381 AN: 26132

East Asian (EAS) AF: 0.00499 AC: 198 AN: 39698

South Asian (SAS) AF: 0.251 AC: 21638 AN: 86250

European-Finnish (FIN) AF: 0.126 AC: 6742 AN: 53402

Middle Eastern (MID) AF: 0.253 AC: 1458 AN: 5768

European-Non Finnish (NFE) AF: 0.149 AC: 165949 AN: 1111812

Other (OTH) AF: 0.166 AC: 9991 AN: 60368

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

African (AFR) AF: 0.185 AC: 7665 AN: 41474

American (AMR) AF: 0.148 AC: 2256 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.251 AC: 871 AN: 3468

East Asian (EAS) AF: 0.0141 AC: 73 AN: 5166

South Asian (SAS) AF: 0.249 AC: 1200 AN: 4816

European-Finnish (FIN) AF: 0.128 AC: 1357 AN: 10590

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.160 AC: 10860 AN: 67972

Other (OTH) AF: 0.187 AC: 395 AN: 2112

Alfa AF: 0.164 Hom.: 8365

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ITGAM-related disorder Benign:1

Nov 12, 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 v4.3

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
PhyloP100		-0.068
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
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: rs1143683; hg19: chr16-31336888; COSMIC: COSV54933565; COSMIC: COSV54933565;