chr16-30499341-G-T

Variant names:

• chr16-30499341-G-T
• rs200068830
• NM_002209.3:c.1997G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002209.3(ITGAL):​c.1997G>T​(p.Arg666Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000044 in 1,613,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. R666H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: ITGAL NM_002209.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.25
• Publications: 2 publications found

Genes affected

ITGAL (HGNC:6148): (integrin subunit alpha L) ITGAL encodes the integrin alpha L 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 the integrin lymphocyte function-associated antigen-1 (LFA-1), which is expressed on all leukocytes. LFA-1 plays a central role in leukocyte intercellular adhesion through interactions with its ligands, ICAMs 1-3 (intercellular adhesion molecules 1 through 3), and also functions in lymphocyte costimulatory signaling. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ITGAL-AS1 (HGNC:56737): (ITGAL antisense RNA 1)

ACMG classification

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=0.050409198).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002209.3. 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
	ITGAL	NM_002209.3	MANE Select	c.1997G>T	p.Arg666Leu	missense	Exon 17 of 31	NP_002200.2	P20701-1
	ITGAL	NM_001114380.2		c.1748G>T	p.Arg583Leu	missense	Exon 15 of 29	NP_001107852.1	P20701-3
	ITGAL-AS1	NR_186415.1		n.191+23C>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGAL	ENST00000356798.11	TSL:1 MANE Select	c.1997G>T	p.Arg666Leu	missense	Exon 17 of 31	ENSP00000349252.5	P20701-1
	ITGAL	ENST00000358164.9	TSL:1	c.1748G>T	p.Arg583Leu	missense	Exon 15 of 29	ENSP00000350886.5	P20701-3
	ITGAL	ENST00000955586.1		c.2003G>T	p.Arg668Leu	missense	Exon 17 of 31	ENSP00000625645.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152074 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251390 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000479 AC: 70 AN: 1461832 Hom.: 0 Cov.: 33 AF XY: 0.0000468 AC XY: 34 AN XY: 727206

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000585 AC: 65 AN: 1111966

Other (OTH) AF: 0.0000331 AC: 2 AN: 60394

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152074 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74268

African (AFR) AF: 0.00 AC: 0 AN: 41400

American (AMR) AF: 0.00 AC: 0 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.0020
DANN	Benign	0.74
DEOGEN2	Benign	0.12	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.050	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.85	L
PhyloP100		-4.3
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.047
Sift	Benign	0.18	T
Sift4G	Benign	0.18	T
Polyphen		0.0	B
Vest4		0.074
MutPred		0.64		Loss of MoRF binding (P = 0.0759)
MVP		0.25
MPC		0.38
ClinPred		0.076	T
GERP RS		-12
Varity_R		0.11
gMVP		0.43
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs200068830; hg19: chr16-30510662; COSMIC: COSV109431094; COSMIC: COSV109431094;