NM_018027.5:c.2134_2146dupCTGGAGTCCCAGG

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRMD4A	NM_018027.5	c.2134_2146dupCTGGAGTCCCAGG	p.Gly716AlafsTer26	frameshift_variant	Exon 22 of 25	ENST00000357447.7	NP_060497.3
FRMD4A	NM_001318337.2	c.2233_2245dupCTGGAGTCCCAGG	p.Gly749AlafsTer26	frameshift_variant	Exon 21 of 24		NP_001305266.1
FRMD4A	NM_001318336.2	c.2182_2194dupCTGGAGTCCCAGG	p.Gly732AlafsTer26	frameshift_variant	Exon 21 of 24		NP_001305265.1
FRMD4A	NM_001318338.2	c.1207_1219dupCTGGAGTCCCAGG	p.Gly407AlafsTer26	frameshift_variant	Exon 11 of 14		NP_001305267.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRMD4A	ENST00000357447.7	c.2134_2146dupCTGGAGTCCCAGG	p.Gly716AlafsTer26	frameshift_variant	Exon 22 of 25	1	NM_018027.5	ENSP00000350032.2
FRMD4A	ENST00000495956.3	c.2134_2146dupCTGGAGTCCCAGG	p.Gly716AlafsTer26	frameshift_variant	Exon 22 of 24	2		ENSP00000488764.2
PRPF18	ENST00000593351.2	n.47+9213_47+9225dupCCTGGGACTCCAG		intron_variant	Intron 1 of 2	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Severe intellectual disability-corpus callosum agenesis-facial dysmorphism-cerebellar ataxia syndrome Pathogenic:1

Feb 21, 2025

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

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;