Genetic Variant FRMD4A:c.*2+5C>T (chr10-13651898-G-A) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

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

Variant links:

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]

FRMD4A links:

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]

PRPF18 links:

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ACMG classification

Classification was made for transcript

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 VariationId is 1175135.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
FRMD4A	NM_018027.5	MANE Select	c.*2+5C>T	splice_region intron	N/A	NP_060497.3
FRMD4A	NM_001318337.2		c.*2+5C>T	splice_region intron	N/A	NP_001305266.1
FRMD4A	NM_001318336.2		c.*2+5C>T	splice_region intron	N/A	NP_001305265.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FRMD4A	ENST00000357447.7	TSL:1 MANE Select	c.*2+5C>T	splice_region intron	N/A	ENSP00000350032.2	Q9P2Q2
FRMD4A	ENST00000495956.3	TSL:2	c.3050+2518C>T	intron	N/A	ENSP00000488764.2	A0A0J9YYA7
PRPF18	ENST00000601460.5	TSL:5	c.577-2455G>A	intron	N/A	ENSP00000473200.1	M0R3G1

Frequencies

GnomAD3 genomes

AF:

0.000526

AC:

AN:

152070

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

Cov.:

AF XY:

0.000763

AC XY:

513

AN XY:

672564

show subpopulations

African (AFR)

AF:

0.000159

AC:

AN:

31446

American (AMR)

AF:

0.000583

AC:

AN:

44608

Ashkenazi Jewish (ASJ)

AF:

0.0000786

AC:

AN:

25440

East Asian (EAS)

AF:

0.0000257

AC:

AN:

38970

South Asian (SAS)

AF:

0.000991

AC:

AN:

83784

European-Finnish (FIN)

AF:

0.0000937

AC:

AN:

53376

Middle Eastern (MID)

AF:

0.000539

AC:

AN:

5564

European-Non Finnish (NFE)

AF:

0.000794

AC:

793

AN:

998262

Other (OTH)

AF:

0.000888

AC:

AN:

56282

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

122

163

204

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000526

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.000470

AC XY:

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.000169

AC:

AN:

41508

American (AMR)

AF:

0.000327

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000208

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000970

AC:

AN:

68008

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000802

Hom.:

Bravo

AF:

0.000612

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.72

PhyloP100

0.34

Mutation Taster

=92/8

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over