12-4525342-G-GTTGT

Variant names:

• chr12-4525342-G-GTTGT
• rs730882197
• NM_020374.4:c.639_640insACAA

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_020374.4(FERRY3):​c.639_640insACAA​(p.Gln214ThrfsTer31) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FERRY3 NM_020374.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 0.550
• Publications: 0 publications found

Genes affected

FERRY3 (HGNC:1184): (FERRY endosomal RAB5 effector complex subunit 3) This gene is highly conserved from nematodes to humans. In rat, the orthologous gene encodes a cytoplasmic protein that is involved in mast cell degranulation. The human gene has been implicated in autosomal recessive intellectual disability. [provided by RefSeq, Sep 2016]

FERRY3 Gene-Disease associations (from GenCC):

• intellectual disability, autosomal recessive 66

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-4525342-G-GTTGT is Pathogenic according to our data. Variant chr12-4525342-G-GTTGT is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 183276.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020374.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FERRY3	NM_020374.4	MANE Select	c.639_640insACAA	p.Gln214ThrfsTer31	frameshift	Exon 6 of 14	NP_065107.1
	FERRY3	NM_001304811.2		c.639_640insACAA	p.Gln214ThrfsTer31	frameshift	Exon 6 of 14	NP_001291740.1
	FERRY3	NM_001346153.2		c.639_640insACAA	p.Gln214ThrfsTer31	frameshift	Exon 6 of 13	NP_001333082.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FERRY3	ENST00000261250.8	TSL:1 MANE Select	c.639_640insACAA	p.Gln214ThrfsTer31	frameshift	Exon 6 of 14	ENSP00000261250.3
	FERRY3	ENST00000545746.5	TSL:1	c.639_640insACAA	p.Gln214ThrfsTer31	frameshift	Exon 6 of 14	ENSP00000439996.1
	FERRY3	ENST00000541014.5	TSL:5	c.120_121insACAA	p.Gln41ThrfsTer31	frameshift	Exon 5 of 8	ENSP00000440820.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Hypotonia;C1263846:Attention deficit hyperactivity disorder;C3714756:Intellectual disability Pathogenic:1

Dec 01, 2014

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Intellectual disability, autosomal recessive 66 Pathogenic:1

Jan 13, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.55
Mutation Taster		=3/197	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs730882197; hg19: chr12-4634508;