rs1143678

Variant names:

• chr16-31331684-C-T
• rs1143678
• NM_000632.4:c.3436C>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.3436C>T​(p.Pro1146Ser) 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 1,606,686 control chromosomes in the GnomAD database, including 20,752 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 0.17 (2395 hom., cov: 31)
  • Exomes 𝑓: 0.15 (18357 hom.)
• Consequence: ITGAM NM_000632.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.22
• Publications: 56 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=0.0047775805).
• BP6: Variant 16-31331684-C-T is Benign according to our data. Variant chr16-31331684-C-T is described in ClinVar as Benign. ClinVar VariationId is 1164969.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.238 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITGAM	NM_000632.4	c.3436C>T	p.Pro1146Ser	missense_variant	Exon 30 of 30	ENST00000544665.9	NP_000623.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGAM	ENST00000544665.9	c.3436C>T	p.Pro1146Ser	missense_variant	Exon 30 of 30	1	NM_000632.4	ENSP00000441691.3
ITGAM	ENST00000648685.1	c.3439C>T	p.Pro1147Ser	missense_variant	Exon 30 of 30			ENSP00000496959.1
ENSG00000289930	ENST00000777754.1	n.571-5976G>A		intron_variant	Intron 2 of 2
ITGAM	ENST00000565142.1	c.*310C>T		downstream_gene_variant		3		ENSP00000461850.1

Frequencies

GnomAD3 genomes AF: 0.170 AC: 25799 AN: 151900 Hom.: 2394 Cov.: 31

Gnomad AFR AF: 0.208

Gnomad AMI AF: 0.193

Gnomad AMR AF: 0.149

Gnomad ASJ AF: 0.223

Gnomad EAS AF: 0.0147

Gnomad SAS AF: 0.249

Gnomad FIN AF: 0.128

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.160

Gnomad OTH AF: 0.187

GnomAD2 exomes AF: 0.154 AC: 36271 AN: 234918 AF XY: 0.161

Gnomad AFR exome AF: 0.211

Gnomad AMR exome AF: 0.103

Gnomad ASJ exome AF: 0.210

Gnomad EAS exome AF: 0.0114

Gnomad FIN exome AF: 0.126

Gnomad NFE exome AF: 0.160

Gnomad OTH exome AF: 0.166

GnomAD4 exome AF: 0.153 AC: 221942 AN: 1454664 Hom.: 18357 Cov.: 33 AF XY: 0.156 AC XY: 112964 AN XY: 722878

African (AFR) AF: 0.216 AC: 7202 AN: 33354

American (AMR) AF: 0.109 AC: 4780 AN: 43850

Ashkenazi Jewish (ASJ) AF: 0.214 AC: 5553 AN: 25908

East Asian (EAS) AF: 0.00481 AC: 190 AN: 39488

South Asian (SAS) AF: 0.250 AC: 21237 AN: 84956

European-Finnish (FIN) AF: 0.126 AC: 6634 AN: 52756

Middle Eastern (MID) AF: 0.252 AC: 1446 AN: 5748

European-Non Finnish (NFE) AF: 0.149 AC: 164959 AN: 1108486

Other (OTH) AF: 0.165 AC: 9941 AN: 60118

GnomAD4 genome AF: 0.170 AC: 25819 AN: 152022 Hom.: 2395 Cov.: 31 AF XY: 0.169 AC XY: 12588 AN XY: 74304

African (AFR) AF: 0.208 AC: 8638 AN: 41470

American (AMR) AF: 0.149 AC: 2281 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.223 AC: 775 AN: 3470

East Asian (EAS) AF: 0.0143 AC: 74 AN: 5158

South Asian (SAS) AF: 0.250 AC: 1200 AN: 4808

European-Finnish (FIN) AF: 0.128 AC: 1360 AN: 10590

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

European-Non Finnish (NFE) AF: 0.160 AC: 10844 AN: 67938

Other (OTH) AF: 0.188 AC: 397 AN: 2110

Alfa AF: 0.170 Hom.: 4967

Bravo AF: 0.170

TwinsUK AF: 0.147 AC: 544

ALSPAC AF: 0.141 AC: 543

ESP6500AA AF: 0.194 AC: 755

ESP6500EA AF: 0.153 AC: 1262

ExAC AF: 0.155 AC: 18676

Asia WGS AF: 0.137 AC: 475 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

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	0.076
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Benign	0.10	.;.;T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.54	.;T;T
MetaRNN	Benign	0.0048	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	.;.;L
PhyloP100		1.2
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.7	.;N;N
REVEL	Benign	0.087
Sift	Uncertain	0.018	.;D;D
Sift4G	Benign	0.087	.;T;T
Polyphen		0.72	.;.;P
Vest4		0.062, 0.22
MPC		0.89
ClinPred		0.023	T
GERP RS		3.3
Varity_R		0.048
gMVP		0.23
Mutation Taster		=89/11	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: rs1143678; hg19: chr16-31343005; COSMIC: COSV54936988; COSMIC: COSV54936988;