10-13651898-G-A

Variant names:

• chr10-13651898-G-A
• rs61754562
• NM_018027.5:c.*2+5C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_018027.5(FRMD4A):​c.*2+5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000703 in 1,489,920 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00072 (2 hom.)
• Consequence: FRMD4A NM_018027.5 splice_region, intron
• Scores: Splicing: ADA: 0.001475
• Clinical Significance: Likely benign no assertion criteria provided B:2
• Conservation: PhyloP100: 0.339
• 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: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 10-13651898-G-A is Benign according to our data. Variant chr10-13651898-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1175135.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRMD4A	NM_018027.5	c.*2+5C>T		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+5C>T		splice_region_variant, intron_variant	Intron 24 of 24	1	NM_018027.5	ENSP00000350032.2

Frequencies

GnomAD3 genomes AF: 0.000526 AC: 80 AN: 152070 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000970

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000748 AC: 188 AN: 251384 AF XY: 0.000795

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00113

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000724 AC: 968 AN: 1337732 Hom.: 2 Cov.: 21 AF XY: 0.000763 AC XY: 513 AN XY: 672564

African (AFR) AF: 0.000159 AC: 5 AN: 31446

American (AMR) AF: 0.000583 AC: 26 AN: 44608

Ashkenazi Jewish (ASJ) AF: 0.0000786 AC: 2 AN: 25440

East Asian (EAS) AF: 0.0000257 AC: 1 AN: 38970

South Asian (SAS) AF: 0.000991 AC: 83 AN: 83784

European-Finnish (FIN) AF: 0.0000937 AC: 5 AN: 53376

Middle Eastern (MID) AF: 0.000539 AC: 3 AN: 5564

European-Non Finnish (NFE) AF: 0.000794 AC: 793 AN: 998262

Other (OTH) AF: 0.000888 AC: 50 AN: 56282

GnomAD4 genome AF: 0.000526 AC: 80 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.000470 AC XY: 35 AN XY: 74396

African (AFR) AF: 0.000169 AC: 7 AN: 41508

American (AMR) AF: 0.000327 AC: 5 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000970 AC: 66 AN: 68008

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

Alfa AF: 0.000802 Hom.: 0

Bravo AF: 0.000612

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: no assertion criteria provided

Submissions by phenotype

not provided Benign:2

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	16
DANN	Benign	0.72
PhyloP100		0.34
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0015
dbscSNV1_RF	Benign	0.014
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs61754562; hg19: chr10-13693898; COSMIC: COSV62267850; COSMIC: COSV62267850;