12-4505374-CC-G

Position:

• chr12-4505374-CC-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The ENST00000261250.8(C12orf4):​c.1168_1169delinsC​(p.Gly390GlnfsTer19) 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 (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: C12orf4 ENST00000261250.8 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.84

Genes affected

C12orf4 (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]

ACMG classification

Verdict is Pathogenic. Variant got 12 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 12-4505374-CC-G is Pathogenic according to our data. Variant chr12-4505374-CC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1708135.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C12orf4	NM_020374.4	c.1168_1169delinsC	p.Gly390GlnfsTer19	frameshift_variant	10/14	ENST00000261250.8	NP_065107.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C12orf4	ENST00000261250.8	c.1168_1169delinsC	p.Gly390GlnfsTer19	frameshift_variant	10/14	1	NM_020374.4	ENSP00000261250	P1
C12orf4	ENST00000545746.5	c.1168_1169delinsC	p.Gly390GlnfsTer19	frameshift_variant	10/14	1		ENSP00000439996	P1
C12orf4	ENST00000509318.2	n.479_480delinsC		non_coding_transcript_exon_variant	2/3	5
C12orf4	ENST00000544258.1	c.52_53delinsC	p.Gly18GlnfsTer19	frameshift_variant, NMD_transcript_variant	2/7	3		ENSP00000444594

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, autosomal recessive 66 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Apr 06, 2022

PVS1, PM2, PP3 -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-4614540;