chr10-13651897-C-T

Variant names:

• chr10-13651897-C-T
• rs549188018
• NM_018027.5:c.*2+6G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_018027.5(FRMD4A):​c.*2+6G>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00000943 in 1,484,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000083 (0 hom.)
• Consequence: FRMD4A NM_018027.5 splice_region, intron
• Scores: Splicing: ADA: 0.7983
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 7.08
• Publications: 0 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_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.23).
• BP6: Variant 10-13651897-C-T is Benign according to our data. Variant chr10-13651897-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3057736.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.*2+6G>A		splice_region_variant, intron_variant	Intron 24 of 24	ENST00000357447.7	NP_060497.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRMD4A	ENST00000357447.7	c.*2+6G>A		splice_region_variant, intron_variant	Intron 24 of 24	1	NM_018027.5	ENSP00000350032.2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000318 AC: 8 AN: 251388 AF XY: 0.0000368

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000826 AC: 11 AN: 1332512 Hom.: 0 Cov.: 22 AF XY: 0.0000149 AC XY: 10 AN XY: 670220

African (AFR) AF: 0.0000956 AC: 3 AN: 31386

American (AMR) AF: 0.00 AC: 0 AN: 44606

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25410

East Asian (EAS) AF: 0.00 AC: 0 AN: 38946

South Asian (SAS) AF: 0.0000239 AC: 2 AN: 83714

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5558

European-Non Finnish (NFE) AF: 0.00000604 AC: 6 AN: 993404

Other (OTH) AF: 0.00 AC: 0 AN: 56118

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152264 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74458

African (AFR) AF: 0.00 AC: 0 AN: 41542

American (AMR) AF: 0.0000654 AC: 1 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

FRMD4A-related disorder Benign:1

Apr 02, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	26
DANN	Benign	0.96
PhyloP100		7.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.80
dbscSNV1_RF	Benign	0.50
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.29		Position offset: 6

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

Other links and lift over

dbSNP: rs549188018; hg19: chr10-13693897;