Genetic Variant NM_001103146.3:c.3855G>A (chr2-232856815-G-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_001103146.3(GIGYF2):c.3855G>A(p.Ser1285Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0181 in 1,613,144 control chromosomes in the GnomAD database, including 332 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.016 ( 28 hom., cov: 32)

Exomes 𝑓: 0.018 ( 304 hom. )

Consequence

GIGYF2
NM_001103146.3 synonymous

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.840

Variant links:

Genes affected

GIGYF2 (HGNC:11960): (GRB10 interacting GYF protein 2) This gene contains CAG trinucleotide repeats and encodes a protein containing several stretches of polyglutamine residues. The encoded protein may be involved in the regulation of tyrosine kinase receptor signaling. This gene is located in a chromosomal region that was genetically linked to Parkinson disease type 11, and mutations in this gene were thought to be causative for this disease. However, more recent studies in different populations have been unable to replicate this association. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2013]

GIGYF2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.56).

BP6

Variant 2-232856815-G-A is Benign according to our data. Variant chr2-232856815-G-A is described in ClinVar as [Benign]. Clinvar id is 3038024.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-232856815-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.84 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0155 (2365/152182) while in subpopulation NFE AF= 0.0193 (1311/68002). AF 95% confidence interval is 0.0184. There are 28 homozygotes in gnomad4. There are 1288 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2365 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GIGYF2	NM_001103146.3 link	c.3855G>A	p.Ser1285Ser	synonymous_variant	Exon 29 of 29	ENST00000373563.9	NP_001096616.1	Q6Y7W6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GIGYF2	ENST00000373563.9 link	c.3855G>A	p.Ser1285Ser	synonymous_variant	Exon 29 of 29	1	NM_001103146.3	ENSP00000362664.5		Q6Y7W6-1

Frequencies

GnomAD3 genomes

AF:

0.0156

AC:

2367

AN:

152064

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00324

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0172

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00497

Gnomad FIN

AF:

0.0563

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0193

Gnomad OTH

AF:

0.0110

GnomAD3 exomes

AF:

0.0168

AC:

4234

AN:

251366

Hom.:

AF XY:

0.0168

AC XY:

2286

AN XY:

135850

show subpopulations

Gnomad AFR exome

AF:

0.00265

Gnomad AMR exome

AF:

0.0119

Gnomad ASJ exome

AF:

0.00645

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00578

Gnomad FIN exome

AF:

0.0589

Gnomad NFE exome

AF:

0.0189

Gnomad OTH exome

AF:

0.0189

GnomAD4 exome

AF:

0.0184

AC:

26888

AN:

1460962

Hom.:

304

Cov.:

AF XY:

0.0181

AC XY:

13126

AN XY:

726860

show subpopulations

Gnomad4 AFR exome

AF:

0.00254

Gnomad4 AMR exome

AF:

0.0120

Gnomad4 ASJ exome

AF:

0.00612

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00519

Gnomad4 FIN exome

AF:

0.0579

Gnomad4 NFE exome

AF:

0.0194

Gnomad4 OTH exome

AF:

0.0158

GnomAD4 genome

AF:

0.0155

AC:

2365

AN:

152182

Hom.:

Cov.:

AF XY:

0.0173

AC XY:

1288

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.00323

Gnomad4 AMR

AF:

0.0172

Gnomad4 ASJ

AF:

0.00346

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00477

Gnomad4 FIN

AF:

0.0563

Gnomad4 NFE

AF:

0.0193

Gnomad4 OTH

AF:

0.0109

Alfa

AF:

0.0163

Hom.:

Bravo

AF:

0.0117

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

GIGYF2-related disorder

Benign:1

Apr 15, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

4.1

DANN

Benign

0.87

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over