Genetic Variant NM_181501.2:c.3363C>A (chr5-52945020-C-A) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_181501.2(ITGA1):c.3363C>A(p.Ser1121Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00793 in 1,611,348 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0058 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0082 ( 66 hom. )

Consequence

ITGA1
NM_181501.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.165

Publications

11 publications found

Variant links:

Genes affected

ITGA1 (HGNC:6134): (integrin subunit alpha 1) This gene encodes the alpha 1 subunit of integrin receptors. This protein heterodimerizes with the beta 1 subunit to form a cell-surface receptor for collagen and laminin. The heterodimeric receptor is involved in cell-cell adhesion and may play a role in inflammation and fibrosis. The alpha 1 subunit contains an inserted (I) von Willebrand factor type I domain which is thought to be involved in collagen binding. [provided by RefSeq, Jul 2008]

ITGA1 links:

ITGA2-AS1 (HGNC:40306): (ITGA2 antisense RNA 1)

ITGA2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005416006).

BP6

Variant 5-52945020-C-A is Benign according to our data. Variant chr5-52945020-C-A is described in ClinVar as Benign. ClinVar VariationId is 720666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 5 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181501.2. 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
	ITGA1	NM_181501.2	MANE Select	c.3363C>A	p.Ser1121Arg	missense	Exon 27 of 29	NP_852478.1	P56199
	ITGA2-AS1	NR_186583.1		n.353+3805G>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ITGA1	ENST00000282588.7	TSL:1 MANE Select	c.3363C>A	p.Ser1121Arg	missense	Exon 27 of 29	ENSP00000282588.5	P56199
ITGA1	ENST00000504669.5	TSL:1	n.6038C>A		non_coding_transcript_exon	Exon 16 of 18
ITGA1	ENST00000506275.1	TSL:1	n.3244C>A		non_coding_transcript_exon	Exon 5 of 7

Frequencies

GnomAD3 genomes

AF:

0.00582

AC:

884

AN:

151998

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00184

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.00996

Gnomad FIN

AF:

0.0108

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00890

Gnomad OTH

AF:

0.00383

GnomAD2 exomes

AF:

0.00691

AC:

1733

AN:

250688

AF XY:

0.00702

show subpopulations

Gnomad AFR exome

AF:

0.00161

Gnomad AMR exome

AF:

0.00191

Gnomad ASJ exome

AF:

0.00229

Gnomad EAS exome

AF:

0.00147

Gnomad FIN exome

AF:

0.0118

Gnomad NFE exome

AF:

0.00886

Gnomad OTH exome

AF:

0.00852

GnomAD4 exome

AF:

0.00816

AC:

11901

AN:

1459232

Hom.:

Cov.:

AF XY:

0.00833

AC XY:

6046

AN XY:

726080

show subpopulations

African (AFR)

AF:

0.00132

AC:

AN:

33340

American (AMR)

AF:

0.00204

AC:

AN:

44664

Ashkenazi Jewish (ASJ)

AF:

0.00230

AC:

AN:

26100

East Asian (EAS)

AF:

0.000808

AC:

AN:

39592

South Asian (SAS)

AF:

0.00978

AC:

843

AN:

86154

European-Finnish (FIN)

AF:

0.0120

AC:

638

AN:

53086

Middle Eastern (MID)

AF:

0.00521

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00882

AC:

9792

AN:

1110226

Other (OTH)

AF:

0.00615

AC:

371

AN:

60308

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

541

1082

1622

2163

2704

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

358

716

1074

1432

1790

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00582

AC:

885

AN:

152116

Hom.:

Cov.:

AF XY:

0.00590

AC XY:

439

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.00183

AC:

AN:

41510

American (AMR)

AF:

0.00124

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3470

East Asian (EAS)

AF:

0.00116

AC:

AN:

5182

South Asian (SAS)

AF:

0.0102

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0108

AC:

114

AN:

10572

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00892

AC:

606

AN:

67954

Other (OTH)

AF:

0.00379

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

143

191

239

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00765

Hom.:

Bravo

AF:

0.00468

TwinsUK

AF:

0.0102

AC:

ALSPAC

AF:

0.00986

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00791

AC:

ExAC

AF:

0.00721

AC:

875

EpiCase

AF:

0.00796

EpiControl

AF:

0.00771

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.055

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.65

MetaRNN

Benign

0.0054

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

PhyloP100

-0.17

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.81

REVEL

Benign

0.064

Sift

Benign

0.21

Sift4G

Uncertain

0.045

Polyphen

0.14

Vest4

0.22

MutPred

0.35

Loss of ubiquitination at K1124 (P = 0.0298)

MVP

0.50

MPC

0.18

ClinPred

0.027

GERP RS

0.42

Varity_R

0.074

gMVP

0.45

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over