Genetic Variant GAREM1:p.Lys291Arg (chr18-32287725-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001242409.2(GAREM1):c.872A>G(p.Lys291Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0101 in 1,614,028 control chromosomes in the GnomAD database, including 350 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 0.010 ( 27 hom., cov: 32)

Exomes 𝑓: 0.010 ( 323 hom. )

Consequence

GAREM1
NM_001242409.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.75

Publications

12 publications found

Variant links:

Genes affected

GAREM1 (HGNC:26136): (GRB2 associated regulator of MAPK1 subtype 1) This gene encodes an adaptor protein which functions in the epidermal growth factor (EGF) receptor-mediated signaling pathway. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

GAREM1 links:

ENSG00000264982 (HGNC:):

ENSG00000264982 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0022611618).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0538 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAREM1	NM_001242409.2 link	c.872A>G	p.Lys291Arg	missense_variant	Exon 4 of 6	ENST00000269209.7	NP_001229338.1	Q9H706-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GAREM1	ENST00000269209.7 link	c.872A>G	p.Lys291Arg	missense_variant	Exon 4 of 6	1	NM_001242409.2	ENSP00000269209.6	Q9H706-1
GAREM1	ENST00000399218.8 link	c.872A>G	p.Lys291Arg	missense_variant	Exon 4 of 6	2		ENSP00000382165.3	Q9H706-3
ENSG00000264982	ENST00000579580.1 link	n.289T>C		non_coding_transcript_exon_variant	Exon 1 of 2	3
GAREM1	ENST00000578619.1 link	n.*151A>G		downstream_gene_variant		4

Frequencies

GnomAD3 genomes

AF:

0.0103

AC:

1562

AN:

152034

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00853

Gnomad AMI

AF:

0.00877

Gnomad AMR

AF:

0.0189

Gnomad ASJ

AF:

0.0118

Gnomad EAS

AF:

0.0594

Gnomad SAS

AF:

0.0299

Gnomad FIN

AF:

0.00669

Gnomad MID

AF:

0.0159

Gnomad NFE

AF:

0.00485

Gnomad OTH

AF:

0.00718

GnomAD2 exomes

AF:

0.0183

AC:

4604

AN:

251482

AF XY:

0.0170

show subpopulations

Gnomad AFR exome

AF:

0.00898

Gnomad AMR exome

AF:

0.0495

Gnomad ASJ exome

AF:

0.0112

Gnomad EAS exome

AF:

0.0510

Gnomad FIN exome

AF:

0.00725

Gnomad NFE exome

AF:

0.00498

Gnomad OTH exome

AF:

0.0111

GnomAD4 exome

AF:

0.0101

AC:

14695

AN:

1461876

Hom.:

323

Cov.:

AF XY:

0.0102

AC XY:

7411

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.00804

AC:

269

AN:

33478

American (AMR)

AF:

0.0468

AC:

2092

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0111

AC:

289

AN:

26136

East Asian (EAS)

AF:

0.0870

AC:

3452

AN:

39700

South Asian (SAS)

AF:

0.0281

AC:

2423

AN:

86248

European-Finnish (FIN)

AF:

0.00580

AC:

310

AN:

53420

Middle Eastern (MID)

AF:

0.0120

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00462

AC:

5141

AN:

1112006

Other (OTH)

AF:

0.0108

AC:

650

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

1081

2162

3243

4324

5405

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

284

568

852

1136

1420

<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:

0.0103

AC:

1570

AN:

152152

Hom.:

Cov.:

AF XY:

0.0104

AC XY:

776

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.00858

AC:

356

AN:

41504

American (AMR)

AF:

0.0190

AC:

290

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.0118

AC:

AN:

3470

East Asian (EAS)

AF:

0.0593

AC:

305

AN:

5142

South Asian (SAS)

AF:

0.0306

AC:

147

AN:

4808

European-Finnish (FIN)

AF:

0.00669

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.0137

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00485

AC:

330

AN:

68026

Other (OTH)

AF:

0.00852

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

156

235

313

391

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.00879

Hom.:

Bravo

AF:

0.0129

TwinsUK

AF:

0.00512

AC:

ALSPAC

AF:

0.00519

AC:

ESP6500AA

AF:

0.0118

AC:

ESP6500EA

AF:

0.00512

AC:

ExAC

AF:

0.0167

AC:

2027

Asia WGS

AF:

0.0560

AC:

195

AN:

3478

EpiCase

AF:

0.00551

EpiControl

AF:

0.00450

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.019

.;T

Eigen

Benign

-0.23

Eigen_PC

Benign

0.0060

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.75

T;T

MetaRNN

Benign

0.0023

T;T

MetaSVM

Benign

-0.98

PhyloP100

4.8

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.56

N;N

REVEL

Benign

0.051

Sift

Benign

0.22

T;T

Sift4G

Benign

0.56

T;T

Polyphen

0.0

B;B

Vest4

0.17

MPC

0.20

ClinPred

0.0071

GERP RS

4.5

Varity_R

0.12

gMVP

0.49

Mutation Taster

=97/3

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