chr10-93694867-C-A

Variant names:

• chr10-93694867-C-A
• rs373087843
• NM_145246.5:c.290G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_145246.5(FRA10AC1):​c.290G>T​(p.Arg97Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000007 in 1,428,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R97H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: FRA10AC1 NM_145246.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.29
• Publications: 0 publications found

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: Ambry Genetics, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.759

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145246.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRA10AC1	NM_145246.5	MANE Select	c.290G>T	p.Arg97Leu	missense	Exon 5 of 14	NP_660289.2
	FRA10AC1	NM_001347712.2		c.290G>T	p.Arg97Leu	missense	Exon 5 of 14	NP_001334641.1	Q70Z53-1
	FRA10AC1	NM_001347713.2		c.290G>T	p.Arg97Leu	missense	Exon 6 of 15	NP_001334642.1	Q70Z53-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRA10AC1	ENST00000359204.5	TSL:1 MANE Select	c.290G>T	p.Arg97Leu	missense	Exon 5 of 14	ENSP00000360488.3	Q70Z53-1
	FRA10AC1	ENST00000905754.1		c.290G>T	p.Arg97Leu	missense	Exon 5 of 14	ENSP00000575813.1
	FRA10AC1	ENST00000905755.1		c.290G>T	p.Arg97Leu	missense	Exon 6 of 15	ENSP00000575814.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 7.00e-7 AC: 1 AN: 1428188 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 712610

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33036

American (AMR) AF: 0.00 AC: 0 AN: 44546

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25924

East Asian (EAS) AF: 0.00 AC: 0 AN: 39488

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85358

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5716

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1081498

Other (OTH) AF: 0.00 AC: 0 AN: 59258

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Uncertain	0.053	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.054	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		5.3
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Benign	0.25
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.74
MutPred		0.43		Gain of ubiquitination at K92 (P = 0.0444)
MVP		0.57
MPC		0.23
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.69
gMVP		0.66
Mutation Taster		=54/46	polymorphism

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

Other links and lift over

dbSNP: rs373087843; hg19: chr10-95454624;