Genetic Variant NM_005544.3:c.2412A>G (chr2-226796327-T-C) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

The NM_005544.3(IRS1):c.2412A>G(p.Ala804Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.127 in 1,613,290 control chromosomes in the GnomAD database, including 20,336 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.20 ( 4769 hom., cov: 33)

Exomes 𝑓: 0.12 ( 15567 hom. )

Consequence

IRS1
NM_005544.3 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -7.31

Publications

47 publications found

Variant links:

Genes affected

IRS1 (HGNC:6125): (insulin receptor substrate 1) This gene encodes a protein which is phosphorylated by insulin receptor tyrosine kinase. Mutations in this gene are associated with type II diabetes and susceptibility to insulin resistance. [provided by RefSeq, Nov 2009]

IRS1 links:

ENSG00000272622 (HGNC:):

ENSG00000272622 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BP7

Synonymous conserved (PhyloP=-7.31 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.411 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
IRS1	NM_005544.3 link	c.2412A>G	p.Ala804Ala	synonymous_variant	Exon 1 of 2	ENST00000305123.6	NP_005535.1
IRS1	XM_047444223.1 link	c.2412A>G	p.Ala804Ala	synonymous_variant	Exon 1 of 2		XP_047300179.1
IRS1	XM_047444224.1 link	c.2412A>G	p.Ala804Ala	synonymous_variant	Exon 1 of 2		XP_047300180.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRS1	ENST00000305123.6 link	c.2412A>G	p.Ala804Ala	synonymous_variant	Exon 1 of 2	1	NM_005544.3	ENSP00000304895.4

Frequencies

GnomAD3 genomes

AF:

0.204

AC:

30985

AN:

152100

Hom.:

4746

Cov.:

show subpopulations

Gnomad AFR

AF:

0.415

Gnomad AMI

AF:

0.0504

Gnomad AMR

AF:

0.224

Gnomad ASJ

AF:

0.189

Gnomad EAS

AF:

0.250

Gnomad SAS

AF:

0.264

Gnomad FIN

AF:

0.0585

Gnomad MID

AF:

0.182

Gnomad NFE

AF:

0.0883

Gnomad OTH

AF:

0.193

GnomAD2 exomes

AF:

0.178

AC:

44542

AN:

250862

AF XY:

0.171

show subpopulations

Gnomad AFR exome

AF:

0.415

Gnomad AMR exome

AF:

0.321

Gnomad ASJ exome

AF:

0.194

Gnomad EAS exome

AF:

0.236

Gnomad FIN exome

AF:

0.0628

Gnomad NFE exome

AF:

0.0890

Gnomad OTH exome

AF:

0.159

GnomAD4 exome

AF:

0.119

AC:

173339

AN:

1461072

Hom.:

15567

Cov.:

AF XY:

0.122

AC XY:

88594

AN XY:

726836

show subpopulations

African (AFR)

AF:

0.432

AC:

14477

AN:

33480

American (AMR)

AF:

0.310

AC:

13844

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.191

AC:

5003

AN:

26136

East Asian (EAS)

AF:

0.259

AC:

10290

AN:

39700

South Asian (SAS)

AF:

0.264

AC:

22741

AN:

86258

European-Finnish (FIN)

AF:

0.0687

AC:

3613

AN:

52616

Middle Eastern (MID)

AF:

0.199

AC:

1146

AN:

5768

European-Non Finnish (NFE)

AF:

0.0839

AC:

93282

AN:

1112002

Other (OTH)

AF:

0.148

AC:

8943

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

10286

20572

30858

41144

51430

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3892

7784

11676

15568

19460

<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:

0.204

AC:

31074

AN:

152218

Hom.:

4769

Cov.:

AF XY:

0.204

AC XY:

15190

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.416

AC:

17268

AN:

41516

American (AMR)

AF:

0.224

AC:

3428

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.189

AC:

657

AN:

3468

East Asian (EAS)

AF:

0.251

AC:

1297

AN:

5168

South Asian (SAS)

AF:

0.264

AC:

1274

AN:

4824

European-Finnish (FIN)

AF:

0.0585

AC:

621

AN:

10620

Middle Eastern (MID)

AF:

0.185

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0883

AC:

6007

AN:

68008

Other (OTH)

AF:

0.200

AC:

422

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1122

2243

3365

4486

5608

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

304

608

912

1216

1520

<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:

0.165

Hom.:

4704

Bravo

AF:

0.226

Asia WGS

AF:

0.279

AC:

968

AN:

3478

EpiCase

AF:

0.100

EpiControl

AF:

0.101

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.052

(source)

DANN

Benign

0.27

PhyloP100

-7.3

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over