rs1143678

Positions:

• chr16-31331684-C-T

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.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. 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.

• 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

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=0.0047775805).
• BP6: Variant 16-31331684-C-T is Benign according to our data. Variant chr16-31331684-C-T is described in ClinVar as [Benign]. Clinvar id is 1164969.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-31331684-C-T is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
ITGAM	NM_000632.4	c.3436C>T	p.Pro1146Ser	missense_variant	30/30	ENST00000544665.9	NP_000623.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITGAM	ENST00000544665.9	c.3436C>T	p.Pro1146Ser	missense_variant	30/30	1	NM_000632.4	ENSP00000441691	P4
ITGAM	ENST00000648685.1	c.3439C>T	p.Pro1147Ser	missense_variant	30/30			ENSP00000496959	A1

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

GnomAD3 exomes AF: 0.154 AC: 36271 AN: 234918 Hom.: 3374 AF XY: 0.161 AC XY: 20602 AN XY: 127708

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 SAS exome AF: 0.250

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

Gnomad4 AFR exome AF: 0.216

Gnomad4 AMR exome AF: 0.109

Gnomad4 ASJ exome AF: 0.214

Gnomad4 EAS exome AF: 0.00481

Gnomad4 SAS exome AF: 0.250

Gnomad4 FIN exome AF: 0.126

Gnomad4 NFE exome AF: 0.149

Gnomad4 OTH exome AF: 0.165

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

Gnomad4 AFR AF: 0.208

Gnomad4 AMR AF: 0.149

Gnomad4 ASJ AF: 0.223

Gnomad4 EAS AF: 0.0143

Gnomad4 SAS AF: 0.250

Gnomad4 FIN AF: 0.128

Gnomad4 NFE AF: 0.160

Gnomad4 OTH AF: 0.188

Alfa AF: 0.171 Hom.: 3605

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

ITGAM-related disorder Benign:1

Benign, no assertion criteria provided

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). -

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
MutationTaster	Benign	1.0	P;P
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

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: rs1143678; hg19: chr16-31343005; COSMIC: COSV54936988; COSMIC: COSV54936988;