Genetic Variant GIGYF1:c.*2348T>C (chr7-100679371-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_001375765.1(GIGYF1):c.*2348T>C variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.225 in 153,182 control chromosomes in the GnomAD database, including 3,927 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 0.22 ( 3888 hom., cov: 32)

Exomes 𝑓: 0.21 ( 39 hom. )

Consequence

GIGYF1
NM_001375765.1 downstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.784

Publications

16 publications found

Variant links:

COSMIC-nc: COSV51947190

Genes affected

GIGYF1 (HGNC:9126): (GRB10 interacting GYF protein 1) This gene encodes a member of the gyf family of adaptor proteins. The encoded protein contains a gyf protein interaction domain. It binds growth factor receptor bound 10, another adaptor protein that binds activated insulin-like growth factor 1 and insulin receptors and regulates receptor signaling. [provided by RefSeq, Apr 2017]

GIGYF1 links:

GNB2 (HGNC:4398): (G protein subunit beta 2) Heterotrimeric guanine nucleotide-binding proteins (G proteins), which integrate signals between receptors and effector proteins, are composed of an alpha, a beta, and a gamma subunit. These subunits are encoded by families of related genes. This gene encodes a beta subunit. Beta subunits are important regulators of alpha subunits, as well as of certain signal transduction receptors and effectors. This gene contains a trinucleotide (CCG) repeat length polymorphism in its 5' UTR. [provided by RefSeq, Jul 2008]

GNB2 Gene-Disease associations (from GenCC):

neurodevelopmental disorder with hypotonia and dysmorphic facies
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
sick sinus syndrome 4
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

GNB2 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 (NFE) allele frequency at 95% confidence interval = 0.243 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GIGYF1	NM_001375765.1 link	c.*2348T>C		downstream_gene_variant		ENST00000678049.1	NP_001362694.1
GNB2	NM_005273.4 link	c.*570A>G		downstream_gene_variant		ENST00000303210.9	NP_005264.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GIGYF1	ENST00000678049.1 link	c.*2348T>C		downstream_gene_variant			NM_001375765.1	ENSP00000503354.1
GNB2	ENST00000303210.9 link	c.*570A>G		downstream_gene_variant		1	NM_005273.4	ENSP00000305260.4

Frequencies

GnomAD3 genomes

AF:

0.225

AC:

34114

AN:

151914

Hom.:

3882

Cov.:

show subpopulations

Gnomad AFR

AF:

0.222

Gnomad AMI

AF:

0.302

Gnomad AMR

AF:

0.182

Gnomad ASJ

AF:

0.197

Gnomad EAS

AF:

0.123

Gnomad SAS

AF:

0.135

Gnomad FIN

AF:

0.265

Gnomad MID

AF:

0.0949

Gnomad NFE

AF:

0.246

Gnomad OTH

AF:

0.190

GnomAD4 exome

AF:

0.211

AC:

243

AN:

1150

Hom.:

AF XY:

0.214

AC XY:

137

AN XY:

640

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AF:

0.160

AC:

AN:

100

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.0769

AC:

AN:

104

European-Finnish (FIN)

AF:

0.279

AC:

AN:

190

Middle Eastern (MID)

AF:

1.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.223

AC:

158

AN:

708

Other (OTH)

AF:

0.176

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.521

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:

0.225

AC:

34153

AN:

152032

Hom.:

3888

Cov.:

AF XY:

0.219

AC XY:

16291

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.222

AC:

9202

AN:

41460

American (AMR)

AF:

0.181

AC:

2770

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.197

AC:

682

AN:

3470

East Asian (EAS)

AF:

0.123

AC:

630

AN:

5140

South Asian (SAS)

AF:

0.137

AC:

663

AN:

4834

European-Finnish (FIN)

AF:

0.265

AC:

2798

AN:

10570

Middle Eastern (MID)

AF:

0.0952

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.246

AC:

16707

AN:

67958

Other (OTH)

AF:

0.188

AC:

398

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

1393

2787

4180

5574

6967

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

358

716

1074

1432

1790

<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:

0.231

Hom.:

5318

Bravo

AF:

0.221

Asia WGS

AF:

0.152

AC:

527

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

0.54

(source)

DANN

Benign

0.41

PhyloP100

-0.78

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