chr10-93681549-A-T

Variant names:

• chr10-93681549-A-T
• rs375390820
• NM_145246.5:c.718T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.445
• 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: G2P, Ambry Genetics

ACMG classification

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	c.718T>A	p.Cys240Ser	missense_variant	Exon 11 of 14	ENST00000359204.5	NP_660289.2

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000913 AC: 2 AN: 218996 AF XY: 0.00000839

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: 3 AN: 1423584 Hom.: 0 Cov.: 27 AF XY: 0.00000141 AC XY: 1 AN XY: 708260

African (AFR) AF: 0.00 AC: 0 AN: 30744

American (AMR) AF: 0.0000549 AC: 2 AN: 36430

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25336

East Asian (EAS) AF: 0.00 AC: 0 AN: 38200

South Asian (SAS) AF: 0.00 AC: 0 AN: 78990

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52242

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5626

European-Non Finnish (NFE) AF: 9.11e-7 AC: 1 AN: 1097252

Other (OTH) AF: 0.00 AC: 0 AN: 58764

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

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	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.074
DANN	Benign	0.21
DEOGEN2	Benign	0.0015	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.035	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.20	N
PhyloP100		0.45
PrimateAI	Benign	0.26	T
PROVEAN	Benign	1.8	N
REVEL	Benign	0.024
Sift	Benign	0.42	T
Sift4G	Benign	0.74	T
Polyphen		0.0	B
Vest4		0.071
MutPred		0.24		Gain of phosphorylation at C240 (P = 3e-04);
MVP		0.12
MPC		0.072
ClinPred		0.022	T
GERP RS		1.8
Varity_R		0.022
gMVP		0.10
Mutation Taster		=91/9	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: rs375390820; hg19: chr10-95441306;