10-13656727-G-T

Position:

chr10-13656727-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_018027.5(FRMD4A):c.2862C>A(p.Asp954Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,439,932 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

FRMD4A
NM_018027.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.49

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 made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.093658835).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
FRMD4A	NM_018027.5 linkuse as main transcript	c.2862C>A	p.Asp954Glu	missense_variant	22/25	ENST00000357447.7	NP_060497.3
FRMD4A	NM_001318337.2 linkuse as main transcript	c.2961C>A	p.Asp987Glu	missense_variant	21/24		NP_001305266.1
FRMD4A	NM_001318336.2 linkuse as main transcript	c.2910C>A	p.Asp970Glu	missense_variant	21/24		NP_001305265.1
FRMD4A	NM_001318338.2 linkuse as main transcript	c.1935C>A	p.Asp645Glu	missense_variant	11/14		NP_001305267.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
FRMD4A	ENST00000357447.7 linkuse as main transcript	c.2862C>A	p.Asp954Glu	missense_variant	22/25	1	NM_018027.5	ENSP00000350032	P2
FRMD4A	ENST00000495956.3 linkuse as main transcript	c.2862C>A	p.Asp954Glu	missense_variant	22/24	2		ENSP00000488764	A2
PRPF18	ENST00000593351.2 linkuse as main transcript	n.47+8497G>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000439

AC:

AN:

227550

Hom.:

AF XY:

0.00000808

AC XY:

AN XY:

123824

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000641

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.94e-7

AC:

AN:

1439932

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

716066

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000269

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2024

The c.2862C>A (p.D954E) alteration is located in exon 22 (coding exon 21) of the FRMD4A gene. This alteration results from a C to A substitution at nucleotide position 2862, causing the aspartic acid (D) at amino acid position 954 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.099

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.042

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.31

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.85

M_CAP

Benign

0.055

MetaRNN

Benign

0.094

MetaSVM

Benign

-0.43

MutationAssessor

Benign

0.81

MutationTaster

Benign

0.94

D;D;D

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-1.5

REVEL

Uncertain

0.29

Sift

Benign

0.030

Sift4G

Benign

0.14

Polyphen

0.0010

Vest4

0.19

MutPred

0.20

Gain of sheet (P = 0.0827);

MVP

0.29

MPC

0.31

ClinPred

0.16

GERP RS

2.2

Varity_R

0.23

gMVP

0.14

Splicing

Name

Calibrated prediction

Score

Prediction

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over