dbSNP rs3791731: GAREM2:c.1683+3184C>A (chr2-26190499-C-A) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The XM_011532567.4(GAREM2):c.1683+3184C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.121 in 152,648 control chromosomes in the GnomAD database, including 2,560 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 0.12 ( 2557 hom., cov: 32)

Exomes 𝑓: 0.048 ( 3 hom. )

Consequence

GAREM2
XM_011532567.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.00

Publications

4 publications found

Variant links:

Genes affected

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

GAREM2 links:

HADHA (HGNC:4801): (hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha) This gene encodes the alpha subunit of the mitochondrial trifunctional protein, which catalyzes the last three steps of mitochondrial beta-oxidation of long chain fatty acids. The mitochondrial membrane-bound heterocomplex is composed of four alpha and four beta subunits, with the alpha subunit catalyzing the 3-hydroxyacyl-CoA dehydrogenase and enoyl-CoA hydratase activities. Mutations in this gene result in trifunctional protein deficiency or LCHAD deficiency. The genes of the alpha and beta subunits of the mitochondrial trifunctional protein are located adjacent to each other in the human genome in a head-to-head orientation. [provided by RefSeq, Jul 2008]

HADHA Gene-Disease associations (from GenCC):

long chain 3-hydroxyacyl-CoA dehydrogenase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
mitochondrial trifunctional protein deficiency
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

HADHA 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 (BayesDel_noAF=-0.93).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.724 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAREM2	XM_011532567.4 link	c.1683+3184C>A		intron_variant	Intron 6 of 6		XP_011530869.1
HADHA	NM_000182.5 link	c.*751G>T		downstream_gene_variant		ENST00000380649.8	NP_000173.2	P40939-1E9KL44

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
HADHA	ENST00000380649.8 link	c.*751G>T	downstream_gene_variant	1	NM_000182.5	ENSP00000370023.3	P40939-1
HADHA	ENST00000492433.2 link	c.*751G>T	downstream_gene_variant	2		ENSP00000438039.2	H0YFD6
HADHA	ENST00000643057.1 link	n.*3021G>T	downstream_gene_variant			ENSP00000493761.1	A0A2R8YDM1
HADHA	ENST00000644428.1 link	n.*1667G>T	downstream_gene_variant			ENSP00000495560.1	A0A2R8YG21

Frequencies

GnomAD3 genomes

AF:

0.121

AC:

18369

AN:

152046

Hom.:

2559

Cov.:

show subpopulations

Gnomad AFR

AF:

0.118

Gnomad AMI

AF:

0.0866

Gnomad AMR

AF:

0.257

Gnomad ASJ

AF:

0.0893

Gnomad EAS

AF:

0.745

Gnomad SAS

AF:

0.0753

Gnomad FIN

AF:

0.0605

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0596

Gnomad OTH

AF:

0.125

GnomAD4 exome

AF:

0.0475

AC:

AN:

484

Hom.:

AF XY:

0.0448

AC XY:

AN XY:

290

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AF:

0.167

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0429

AC:

AN:

420

Other (OTH)

AF:

0.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.121

AC:

18376

AN:

152164

Hom.:

2557

Cov.:

AF XY:

0.126

AC XY:

9403

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.118

AC:

4900

AN:

41526

American (AMR)

AF:

0.257

AC:

3935

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0893

AC:

310

AN:

3470

East Asian (EAS)

AF:

0.744

AC:

3837

AN:

5158

South Asian (SAS)

AF:

0.0747

AC:

361

AN:

4830

European-Finnish (FIN)

AF:

0.0605

AC:

641

AN:

10598

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0596

AC:

4050

AN:

67974

Other (OTH)

AF:

0.122

AC:

258

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

671

1342

2012

2683

3354

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

186

372

558

744

930

<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:

0.0806

Hom.:

1468

Bravo

AF:

0.143

Asia WGS

AF:

0.331

AC:

1150

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.089

(source)

DANN

Benign

0.53

PhyloP100

-2.0

Splicing

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