Genetic Variant NM_004627.6:c.*425A>G (chr21-39397364-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_004627.6(GET1):c.*425A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.655 in 158,334 control chromosomes in the GnomAD database, including 34,477 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 0.65 ( 32999 hom., cov: 33)

Exomes 𝑓: 0.68 ( 1478 hom. )

Consequence

GET1
NM_004627.6 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.84

Publications

13 publications found

Variant links:

Genes affected

GET1 (HGNC:12790): (guided entry of tail-anchored proteins factor 1) This gene is located in the candidate region for congenital heart disease (CHD) in Down syndrome (DS). It encodes a basic protein that functions as a receptor that promotes insertion of tail-anchored proteins in the endoplasmic reticulum membrane. This gene is located at a maternally-methylated differentially methylated region (DMR); however, its transcription may be biallelic, not imprinted. Alternative splicing results in different transcript variants. A pseudogene has been defined on chromosome 4. [provided by RefSeq, Apr 2017]

GET1 links:

GET1-SH3BGR (HGNC:54635): (GET1-SH3BGR readthrough) This locus represents naturally occurring readthrough transcription between the neighboring WRB (tryptophan rich basic protein) and SH3BGR (SH3 domain binding glutamate-rich protein) genes on chromosome 21. Readthrough transcripts may encode fusion proteins that shares sequence identity with each individual gene product. [provided by RefSeq, Apr 2017]

GET1-SH3BGR links:

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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=-0.65).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.754 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GET1	NM_004627.6 link	c.*425A>G		3_prime_UTR_variant	Exon 5 of 5	ENST00000649170.1	NP_004618.2	O00258-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GET1	ENST00000649170.1 link	c.*425A>G		3_prime_UTR_variant	Exon 5 of 5		NM_004627.6	ENSP00000496813.1		O00258-1
GET1-SH3BGR	ENST00000647779.1 link	c.336+5528A>G		intron_variant	Intron 3 of 8			ENSP00000497977.1		A0A3B3ITX9

Frequencies

GnomAD3 genomes

AF:

0.654

AC:

99409

AN:

151986

Hom.:

32964

Cov.:

show subpopulations

Gnomad AFR

AF:

0.538

Gnomad AMI

AF:

0.739

Gnomad AMR

AF:

0.693

Gnomad ASJ

AF:

0.655

Gnomad EAS

AF:

0.775

Gnomad SAS

AF:

0.711

Gnomad FIN

AF:

0.779

Gnomad MID

AF:

0.617

Gnomad NFE

AF:

0.682

Gnomad OTH

AF:

0.673

GnomAD4 exome

AF:

0.685

AC:

4266

AN:

6230

Hom.:

1478

Cov.:

AF XY:

0.679

AC XY:

2177

AN XY:

3204

show subpopulations

African (AFR)

AF:

0.549

AC:

AN:

102

American (AMR)

AF:

0.715

AC:

379

AN:

530

Ashkenazi Jewish (ASJ)

AF:

0.677

AC:

107

AN:

158

East Asian (EAS)

AF:

0.807

AC:

121

AN:

150

South Asian (SAS)

AF:

0.679

AC:

349

AN:

514

European-Finnish (FIN)

AF:

0.763

AC:

151

AN:

198

Middle Eastern (MID)

AF:

0.583

AC:

AN:

European-Non Finnish (NFE)

AF:

0.678

AC:

2857

AN:

4212

Other (OTH)

AF:

0.675

AC:

239

AN:

354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

140

209

279

349

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<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:

0.654

AC:

99496

AN:

152104

Hom.:

32999

Cov.:

AF XY:

0.662

AC XY:

49243

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.539

AC:

22348

AN:

41496

American (AMR)

AF:

0.694

AC:

10586

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.655

AC:

2272

AN:

3468

East Asian (EAS)

AF:

0.774

AC:

4010

AN:

5178

South Asian (SAS)

AF:

0.710

AC:

3424

AN:

4820

European-Finnish (FIN)

AF:

0.779

AC:

8236

AN:

10568

Middle Eastern (MID)

AF:

0.605

AC:

178

AN:

294

European-Non Finnish (NFE)

AF:

0.682

AC:

46346

AN:

67990

Other (OTH)

AF:

0.673

AC:

1422

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1796

3591

5387

7182

8978

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

804

1608

2412

3216

4020

<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:

0.662

Hom.:

15276

Bravo

AF:

0.645

Asia WGS

AF:

0.750

AC:

2609

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Benign

0.73

PhyloP100

1.8

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