17-3753881-T-C

Position:

• chr17-3753881-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002208.5(ITGAE):​c.1429A>G​(p.Ile477Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.792 in 1,613,688 control chromosomes in the GnomAD database, including 515,181 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I477T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.82 (52670 hom., cov: 33)
  • Exomes 𝑓: 0.79 (462511 hom.)
• Consequence: ITGAE NM_002208.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.567

Genes affected

ITGAE (HGNC:6147): (integrin subunit alpha E) Integrins are heterodimeric integral membrane proteins composed of an alpha chain and a beta chain. This gene encodes an I-domain-containing alpha integrin that undergoes post-translational cleavage in the extracellular domain, yielding disulfide-linked heavy and light chains. In combination with the beta 7 integrin, this protein forms the E-cadherin binding integrin known as the human mucosal lymphocyte-1 antigen. This protein is preferentially expressed in human intestinal intraepithelial lymphocytes (IEL), and in addition to a role in adhesion, it may serve as an accessory molecule for IEL activation. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.5543226E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.953 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGAE	NM_002208.5	c.1429A>G	p.Ile477Val	missense_variant	13/31	ENST00000263087.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGAE	ENST00000263087.9	c.1429A>G	p.Ile477Val	missense_variant	13/31	1	NM_002208.5	P1
ITGAE	ENST00000572121.1	n.110A>G		non_coding_transcript_exon_variant	2/4	5

Frequencies

GnomAD3 genomes AF: 0.822 AC: 124917 AN: 151916 Hom.: 52615 Cov.: 33

Gnomad AFR AF: 0.961

Gnomad AMI AF: 0.812

Gnomad AMR AF: 0.686

Gnomad ASJ AF: 0.753

Gnomad EAS AF: 0.406

Gnomad SAS AF: 0.541

Gnomad FIN AF: 0.852

Gnomad MID AF: 0.777

Gnomad NFE AF: 0.820

Gnomad OTH AF: 0.794

GnomAD3 exomes AF: 0.729 AC: 182961 AN: 251106 Hom.: 69937 AF XY: 0.723 AC XY: 98185 AN XY: 135732

Gnomad AFR exome AF: 0.967

Gnomad AMR exome AF: 0.574

Gnomad ASJ exome AF: 0.761

Gnomad EAS exome AF: 0.377

Gnomad SAS exome AF: 0.555

Gnomad FIN exome AF: 0.854

Gnomad NFE exome AF: 0.817

Gnomad OTH exome AF: 0.757

GnomAD4 exome AF: 0.788 AC: 1152380 AN: 1461654 Hom.: 462511 Cov.: 58 AF XY: 0.781 AC XY: 567573 AN XY: 727146

Gnomad4 AFR exome AF: 0.970

Gnomad4 AMR exome AF: 0.586

Gnomad4 ASJ exome AF: 0.761

Gnomad4 EAS exome AF: 0.418

Gnomad4 SAS exome AF: 0.553

Gnomad4 FIN exome AF: 0.851

Gnomad4 NFE exome AF: 0.821

Gnomad4 OTH exome AF: 0.776

GnomAD4 genome AF: 0.822 AC: 125034 AN: 152034 Hom.: 52670 Cov.: 33 AF XY: 0.813 AC XY: 60372 AN XY: 74282

Gnomad4 AFR AF: 0.961

Gnomad4 AMR AF: 0.685

Gnomad4 ASJ AF: 0.753

Gnomad4 EAS AF: 0.406

Gnomad4 SAS AF: 0.541

Gnomad4 FIN AF: 0.852

Gnomad4 NFE AF: 0.820

Gnomad4 OTH AF: 0.793

Alfa AF: 0.807 Hom.: 43399

Bravo AF: 0.816

TwinsUK AF: 0.811 AC: 3008

ALSPAC AF: 0.815 AC: 3142

ESP6500AA AF: 0.956 AC: 4210

ESP6500EA AF: 0.817 AC: 7022

ExAC AF: 0.736 AC: 89309

Asia WGS AF: 0.522 AC: 1817 AN: 3478

EpiCase AF: 0.814

EpiControl AF: 0.809

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.025
DANN	Benign	0.24
DEOGEN2	Benign	0.052	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0025	N
LIST_S2	Benign	0.13	T
MetaRNN	Benign	0.0000016	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.2	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.30	N
REVEL	Benign	0.0040
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.015
MPC		0.13
ClinPred		0.0036	T
GERP RS		-3.8
Varity_R		0.019
gMVP		0.64

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: rs220479; hg19: chr17-3657175; COSMIC: COSV53993148;