rs869025338

Variant names:

• chr10-13657442-C-CCCTGGGACTCCAG
• rs869025338
• NM_018027.5:c.2134_2146dupCTGGAGTCCCAGG

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_018027.5(FRMD4A):​c.2134_2146dupCTGGAGTCCCAGG​(p.Gly716AlafsTer26) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FRMD4A NM_018027.5 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.95
• Publications: 1 publications found

Genes affected

FRMD4A (HGNC:25491): (FERM domain containing 4A) This gene encodes a FERM domain-containing protein that regulates epithelial cell polarity. It connects ADP ribosylation factor 6 (ARF6) with the Par protein complex, which regulates the remodeling of adherens junctions and linear actin cable formation during epithelial cell polarization. Polymorphisms in this gene are associated with Alzheimer's disease, and also with nicotine dependence. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

PRPF18 (HGNC:17351): (pre-mRNA processing factor 18) Pre-mRNA splicing occurs in 2 sequential transesterification steps. The protein encoded by this gene is found to be essential for the catalytic step II in pre-mRNA splicing process. It is found in the spliceosome, and contains seven WD repeats, which function in protein-protein interactions. This protein has a sequence similarity to the yeast splicing factor Prp18. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 10-13657442-C-CCCTGGGACTCCAG is Pathogenic according to our data. Variant chr10-13657442-C-CCCTGGGACTCCAG is described in ClinVar as Pathogenic. ClinVar VariationId is 222035.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018027.5. 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
	FRMD4A	NM_018027.5	MANE Select	c.2134_2146dupCTGGAGTCCCAGG	p.Gly716AlafsTer26	frameshift	Exon 22 of 25	NP_060497.3
	FRMD4A	NM_001318337.2		c.2233_2245dupCTGGAGTCCCAGG	p.Gly749AlafsTer26	frameshift	Exon 21 of 24	NP_001305266.1
	FRMD4A	NM_001318336.2		c.2182_2194dupCTGGAGTCCCAGG	p.Gly732AlafsTer26	frameshift	Exon 21 of 24	NP_001305265.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRMD4A	ENST00000357447.7	TSL:1 MANE Select	c.2134_2146dupCTGGAGTCCCAGG	p.Gly716AlafsTer26	frameshift	Exon 22 of 25	ENSP00000350032.2	Q9P2Q2
	FRMD4A	ENST00000495956.3	TSL:2	c.2134_2146dupCTGGAGTCCCAGG	p.Gly716AlafsTer26	frameshift	Exon 22 of 24	ENSP00000488764.2	A0A0J9YYA7
	PRPF18	ENST00000593351.2	TSL:5	n.47+9213_47+9225dupCCTGGGACTCCAG		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Severe intellectual disability-corpus callosum agenesis-facial dysmorphism-cerebellar ataxia syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.0
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs869025338; hg19: chr10-13699442;