Genetic Variant NM_145246.5:c.718T>A (chr10-93681549-A-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_145246.5(FRA10AC1):c.718T>A(p.Cys240Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000211 in 1,423,584 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C240G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

FRA10AC1
NM_145246.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.445

Publications

0 publications found

Variant links:

Genes affected

FRA10AC1 (HGNC:1162): (FRA10A associated CGG repeat 1) The protein encoded by this gene is a nuclear phosphoprotein of unknown function. This gene contains a tandem CGG repeat region within a CpG island that normally consists of 8-14 repeats but can expand to over 200 repeats. The repeat region is within the 5' UTR of some transcript variants, but is intronic to another variant. The expanded repeat allele is a fragile site and becomes hypermethylated, causing a reduction in gene expression. A disease phenotype has not been associated with expanded alleles. This gene is found within the rare FRA10A folate-sensitive fragile site. [provided by RefSeq, Dec 2016]

FRA10AC1 Gene-Disease associations (from GenCC):

neurodevelopmental disorder with growth retardation, dysmorphic facies, and corpus callosum abnormalities
Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics

FRA10AC1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.03474632).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRA10AC1	NM_145246.5 link	c.718T>A	p.Cys240Ser	missense_variant	Exon 11 of 14	ENST00000359204.5	NP_660289.2	Q70Z53-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRA10AC1	ENST00000359204.5 link	c.718T>A	p.Cys240Ser	missense_variant	Exon 11 of 14	1	NM_145246.5	ENSP00000360488.3		Q70Z53-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000913

AC:

AN:

218996

AF XY:

0.00000839

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000777

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.00000211

AC:

AN:

1423584

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

708260

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30744

American (AMR)

AF:

0.0000549

AC:

AN:

36430

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25336

East Asian (EAS)

AF:

0.00

AC:

AN:

38200

South Asian (SAS)

AF:

0.00

AC:

AN:

78990

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52242

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5626

European-Non Finnish (NFE)

AF:

9.11e-7

AC:

AN:

1097252

Other (OTH)

AF:

0.00

AC:

AN:

58764

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.62

CADD

Benign

0.074

(source)

DANN

Benign

0.21

DEOGEN2

Benign

0.0015

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.037

LIST_S2

Benign

0.38

M_CAP

Benign

0.0058

MetaRNN

Benign

0.035

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.20

PhyloP100

0.45

PrimateAI

Benign

0.26

PROVEAN

Benign

1.8

REVEL

Benign

0.024

Sift

Benign

0.42

Sift4G

Benign

0.74

Polyphen

0.0

Vest4

0.071

MutPred

0.24

Gain of phosphorylation at C240 (P = 3e-04);

MVP

0.12

MPC

0.072

ClinPred

0.022

GERP RS

1.8

Varity_R

0.022

gMVP

0.10

Mutation Taster

=91/9

polymorphism

(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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NM_145246.5:c.718T>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over