Genetic Variant ITGAM:p.Leu3His (chr16-31260072-T-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000632.4(ITGAM):c.8T>A(p.Leu3His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L3F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ITGAM
NM_000632.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.924

Publications

0 publications found

Variant links:

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

ITGAM links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.065816075).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGAM	NM_000632.4	MANE Select	c.8T>A	p.Leu3His	missense	Exon 1 of 30	NP_000623.2	P11215-1
	ITGAM	NM_001145808.2		c.8T>A	p.Leu3His	missense	Exon 1 of 30	NP_001139280.1	P11215-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ITGAM	ENST00000544665.9	TSL:1 MANE Select	c.8T>A	p.Leu3His	missense	Exon 1 of 30	ENSP00000441691.3	P11215-1
ITGAM	ENST00000943361.1		c.8T>A	p.Leu3His	missense	Exon 1 of 30	ENSP00000613420.1
ITGAM	ENST00000648685.1		c.8T>A	p.Leu3His	missense	Exon 1 of 30	ENSP00000496959.1	P11215-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1186990

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

586204

African (AFR)

AF:

0.00

AC:

AN:

26140

American (AMR)

AF:

0.00

AC:

AN:

33694

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16698

East Asian (EAS)

AF:

0.00

AC:

AN:

17260

South Asian (SAS)

AF:

0.00

AC:

AN:

79216

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4472

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

934520

Other (OTH)

AF:

0.00

AC:

AN:

43582

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

2.0

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.052

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.028

LIST_S2

Benign

0.29

M_CAP

Benign

0.014

MetaRNN

Benign

0.066

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PhyloP100

-0.92

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.6

REVEL

Benign

0.090

Sift

Benign

0.35

Sift4G

Benign

0.65

Polyphen

0.0

Vest4

0.26

MutPred

0.60

Loss of stability (P = 0.0012)

MVP

0.23

MPC

0.37

ClinPred

0.073

GERP RS

-4.7

PromoterAI

-0.024

Neutral

(source)

Varity_R

0.063

gMVP

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over