Genetic Variant GIGYF1:c.3056-8G>T (chr7-100681779-C-A) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_001375759.1(GIGYF1):c.3140G>T(p.Arg1047Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00163 in 1,589,766 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 7/7 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.0083 ( 16 hom., cov: 33)

Exomes 𝑓: 0.00092 ( 22 hom. )

Consequence

GIGYF1
NM_001375759.1 missense

Scores

Splicing: ADA: 0.0002998

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.328

Publications

0 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
neurodevelopmental disorder
Inheritance: AD Classification: MODERATE Submitted by: G2P

GIGYF1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BP6

Variant 7-100681779-C-A is Benign according to our data. Variant chr7-100681779-C-A is described in ClinVar as Benign. ClinVar VariationId is 3040354.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00832 (1268/152316) while in subpopulation AFR AF = 0.0294 (1224/41562). AF 95% confidence interval is 0.0281. There are 16 homozygotes in GnomAd4. There are 568 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 1268 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001375759.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GIGYF1	NM_001375765.1	MANE Select	c.3056-8G>T		splice_region intron	N/A	NP_001362694.1	O75420
GIGYF1	NM_001375759.1		c.3140G>T	p.Arg1047Leu	missense	Exon 26 of 26	NP_001362688.1
GIGYF1	NM_001375760.1		c.3140G>T	p.Arg1047Leu	missense	Exon 26 of 26	NP_001362689.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GIGYF1	ENST00000678049.1	MANE Select	c.3056-8G>T	splice_region intron	N/A	ENSP00000503354.1	O75420
GIGYF1	ENST00000275732.5	TSL:1	c.3056-8G>T	splice_region intron	N/A	ENSP00000275732.4	O75420
GIGYF1	ENST00000893817.1		c.3089-8G>T	splice_region intron	N/A	ENSP00000563876.1

Frequencies

GnomAD3 genomes

AF:

0.00832

AC:

1267

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0295

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00209

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:

0.000103

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00243

AC:

562

AN:

231172

AF XY:

0.00183

show subpopulations

Gnomad AFR exome

AF:

0.0320

Gnomad AMR exome

AF:

0.000966

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000671

Gnomad OTH exome

AF:

0.00197

GnomAD4 exome

AF:

0.000918

AC:

1320

AN:

1437450

Hom.:

Cov.:

AF XY:

0.000824

AC XY:

587

AN XY:

712384

show subpopulations

African (AFR)

AF:

0.0326

AC:

1078

AN:

33030

American (AMR)

AF:

0.00144

AC:

AN:

42310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24234

East Asian (EAS)

AF:

0.00

AC:

AN:

39450

South Asian (SAS)

AF:

0.0000484

AC:

AN:

82656

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52226

Middle Eastern (MID)

AF:

0.000889

AC:

AN:

5624

European-Non Finnish (NFE)

AF:

0.0000146

AC:

AN:

1098698

Other (OTH)

AF:

0.00263

AC:

156

AN:

59222

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

143

214

286

357

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<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:

0.00832

AC:

1268

AN:

152316

Hom.:

Cov.:

AF XY:

0.00763

AC XY:

568

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.0295

AC:

1224

AN:

41562

American (AMR)

AF:

0.00209

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68024

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

133

200

266

333

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00468

Hom.:

Bravo

AF:

0.00977

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

GIGYF1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.87

PhyloP100

0.33

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00030

dbscSNV1_RF

Benign

0.0080

SpliceAI score (max)

0.070

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over