Genetic Variant GAREM2:p.Ala311Thr (chr2-26184779-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001168241.2(GAREM2):c.931G>A(p.Ala311Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000253 in 1,500,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

GAREM2
NM_001168241.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.873

Publications

0 publications found

Variant links:

Genes affected

GAREM2 (HGNC:27172): (GRB2 associated regulator of MAPK1 subtype 2)

GAREM2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=0.03910473).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAREM2	NM_001168241.2 link	c.931G>A	p.Ala311Thr	missense_variant	Exon 4 of 6	ENST00000401533.7	NP_001161713.1	Q75VX8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAREM2	ENST00000401533.7 link	c.931G>A	p.Ala311Thr	missense_variant	Exon 4 of 6	1	NM_001168241.2	ENSP00000384593.1		Q75VX8-1
GAREM2	ENST00000407684.1 link	c.700G>A	p.Ala234Thr	missense_variant	Exon 3 of 6	2		ENSP00000384581.1		Q75VX8-3

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151928

Hom.:

Cov.:

show subpopulations

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000208

AC:

AN:

96324

AF XY:

0.0000371

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000563

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000267

AC:

AN:

1348116

Hom.:

Cov.:

AF XY:

0.0000196

AC XY:

AN XY:

663930

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27646

American (AMR)

AF:

0.00

AC:

AN:

31388

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23940

East Asian (EAS)

AF:

0.00

AC:

AN:

30916

South Asian (SAS)

AF:

0.00

AC:

AN:

75580

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5596

European-Non Finnish (NFE)

AF:

0.0000329

AC:

AN:

1063154

Other (OTH)

AF:

0.0000178

AC:

AN:

56276

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151928

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74212

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41422

American (AMR)

AF:

0.00

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10510

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67952

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 02, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.931G>A (p.A311T) alteration is located in exon 4 (coding exon 4) of the GAREM2 gene. This alteration results from a G to A substitution at nucleotide position 931, causing the alanine (A) at amino acid position 311 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.011

T;.

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.82

T;T

M_CAP

Uncertain

0.086

MetaRNN

Benign

0.039

T;T

MetaSVM

Benign

-0.98

PhyloP100

0.87

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-0.69

N;N

REVEL

Benign

0.094

Sift

Benign

0.34

T;T

Sift4G

Benign

0.64

T;T

Polyphen

0.020

B;.

Vest4

0.12

MutPred

0.24

Gain of glycosylation at A311 (P = 0.0418);.;

MVP

0.067

ClinPred

0.083

GERP RS

2.5

Varity_R

0.059

gMVP

0.26

Mutation Taster

=97/3

polymorphism

(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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2-26184779-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over