Genetic Variant FRMD4A:c.760-6150T>C (chr10-13713263-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_018027.5(FRMD4A):c.760-6150T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.908 in 152,202 control chromosomes in the GnomAD database, including 62,749 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.91 ( 62749 hom., cov: 31)

Consequence

FRMD4A
NM_018027.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.142

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 Gene-Disease associations (from GenCC):

severe intellectual disability-corpus callosum agenesis-facial dysmorphism-cerebellar ataxia syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

FRMD4A links:

ENSG00000225112 (HGNC:):

ENSG00000225112 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

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.760-6150T>C	intron	N/A	NP_060497.3
FRMD4A	NM_001318337.2		c.859-6150T>C	intron	N/A	NP_001305266.1
FRMD4A	NM_001318336.2		c.808-6150T>C	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.760-6150T>C	intron	N/A	ENSP00000350032.2	Q9P2Q2
FRMD4A	ENST00000495956.3	TSL:2	c.760-6150T>C	intron	N/A	ENSP00000488764.2	A0A0J9YYA7
FRMD4A	ENST00000264546.10	TSL:2	c.859-6150T>C	intron	N/A	ENSP00000264546.6	Q5T376

Frequencies

GnomAD3 genomes

AF:

0.908

AC:

138058

AN:

152084

Hom.:

62710

Cov.:

show subpopulations

Gnomad AFR

AF:

0.921

Gnomad AMI

AF:

0.897

Gnomad AMR

AF:

0.910

Gnomad ASJ

AF:

0.901

Gnomad EAS

AF:

0.999

Gnomad SAS

AF:

0.912

Gnomad FIN

AF:

0.886

Gnomad MID

AF:

0.905

Gnomad NFE

AF:

0.896

Gnomad OTH

AF:

0.910

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.908

AC:

138155

AN:

152202

Hom.:

62749

Cov.:

AF XY:

0.908

AC XY:

67576

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.921

AC:

38232

AN:

41528

American (AMR)

AF:

0.910

AC:

13905

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.901

AC:

3128

AN:

3470

East Asian (EAS)

AF:

0.999

AC:

5174

AN:

5180

South Asian (SAS)

AF:

0.912

AC:

4390

AN:

4814

European-Finnish (FIN)

AF:

0.886

AC:

9389

AN:

10594

Middle Eastern (MID)

AF:

0.905

AC:

266

AN:

294

European-Non Finnish (NFE)

AF:

0.896

AC:

60931

AN:

68010

Other (OTH)

AF:

0.910

AC:

1922

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

638

1277

1915

2554

3192

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

904

1808

2712

3616

4520

<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:

0.903

Hom.:

12583

Bravo

AF:

0.910

Asia WGS

AF:

0.961

AC:

3342

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

5.2

(source)

DANN

Benign

0.85

PhyloP100

0.14

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over