7-100681721-A-C

Variant names:

• chr7-100681721-A-C
• rs1163941038
• NM_001375765.1:c.3106T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM4 PP5_Moderate

The NM_001375765.1(GIGYF1):​c.3106T>G​(p.Ter1036Glyext*?) variant causes a stop lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GIGYF1 NM_001375765.1 stop_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.02
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_001375765.1 Downstream stopcodon found after 21 codons.
• PP5: Variant 7-100681721-A-C is Pathogenic according to our data. Variant chr7-100681721-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 2430005.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001375765.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GIGYF1	NM_001375765.1	MANE Select	c.3106T>G	p.Ter1036Glyext*?	stop_lost	Exon 27 of 27	NP_001362694.1	O75420
	GIGYF1	NM_001375766.1		c.3106T>G	p.Ter1036Glyext*?	stop_lost	Exon 28 of 28	NP_001362695.1	O75420
	GIGYF1	NM_001375759.1		c.3198T>G	p.Thr1066Thr	synonymous	Exon 26 of 26	NP_001362688.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GIGYF1	ENST00000678049.1	MANE Select	c.3106T>G	p.Ter1036Glyext*?	stop_lost	Exon 27 of 27	ENSP00000503354.1	O75420
	GIGYF1	ENST00000275732.5	TSL:1	c.3106T>G	p.Ter1036Glyext*?	stop_lost	Exon 24 of 24	ENSP00000275732.4	O75420
	GIGYF1	ENST00000893817.1		c.3139T>G	p.Ter1047Glyext*?	stop_lost	Exon 27 of 27	ENSP00000563876.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Autism spectrum disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	14
DANN	Benign	0.92
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.97	D
PhyloP100		4.0
Vest4		0.094
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=10/190	disease causing

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

Other links and lift over

dbSNP: rs1163941038; hg19: chr7-100279344;