rs726817

Positions:

• chr10-93700060-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_145246.5(FRA10AC1):​c.47G>A​(p.Arg16His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.715 in 1,593,118 control chromosomes in the GnomAD database, including 410,478 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.66 (34094 hom., cov: 32)
  • Exomes 𝑓: 0.72 (376384 hom.)
• Consequence: FRA10AC1 NM_145246.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.331

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.96175E-7).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.729 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FRA10AC1	NM_145246.5	c.47G>A	p.Arg16His	missense_variant	2/14	ENST00000359204.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FRA10AC1	ENST00000359204.5	c.47G>A	p.Arg16His	missense_variant	2/14	1	NM_145246.5	P1

Frequencies

GnomAD3 genomes AF: 0.662 AC: 100559 AN: 151930 Hom.: 34077 Cov.: 32

Gnomad AFR AF: 0.505

Gnomad AMI AF: 0.721

Gnomad AMR AF: 0.685

Gnomad ASJ AF: 0.816

Gnomad EAS AF: 0.699

Gnomad SAS AF: 0.626

Gnomad FIN AF: 0.711

Gnomad MID AF: 0.775

Gnomad NFE AF: 0.734

Gnomad OTH AF: 0.684

GnomAD3 exomes AF: 0.701 AC: 173370 AN: 247310 Hom.: 61502 AF XY: 0.704 AC XY: 94215 AN XY: 133888

Gnomad AFR exome AF: 0.499

Gnomad AMR exome AF: 0.690

Gnomad ASJ exome AF: 0.812

Gnomad EAS exome AF: 0.713

Gnomad SAS exome AF: 0.638

Gnomad FIN exome AF: 0.706

Gnomad NFE exome AF: 0.736

Gnomad OTH exome AF: 0.719

GnomAD4 exome AF: 0.721 AC: 1038459 AN: 1441070 Hom.: 376384 Cov.: 29 AF XY: 0.720 AC XY: 516745 AN XY: 717840

Gnomad4 AFR exome AF: 0.494

Gnomad4 AMR exome AF: 0.687

Gnomad4 ASJ exome AF: 0.813

Gnomad4 EAS exome AF: 0.705

Gnomad4 SAS exome AF: 0.640

Gnomad4 FIN exome AF: 0.709

Gnomad4 NFE exome AF: 0.734

Gnomad4 OTH exome AF: 0.719

GnomAD4 genome AF: 0.662 AC: 100617 AN: 152048 Hom.: 34094 Cov.: 32 AF XY: 0.659 AC XY: 49014 AN XY: 74330

Gnomad4 AFR AF: 0.505

Gnomad4 AMR AF: 0.684

Gnomad4 ASJ AF: 0.816

Gnomad4 EAS AF: 0.699

Gnomad4 SAS AF: 0.627

Gnomad4 FIN AF: 0.711

Gnomad4 NFE AF: 0.734

Gnomad4 OTH AF: 0.683

Alfa AF: 0.727 Hom.: 94333

Bravo AF: 0.658

TwinsUK AF: 0.736 AC: 2729

ALSPAC AF: 0.736 AC: 2837

ESP6500AA AF: 0.510 AC: 2247

ESP6500EA AF: 0.742 AC: 6382

ExAC AF: 0.697 AC: 84621

Asia WGS AF: 0.657 AC: 2286 AN: 3476

EpiCase AF: 0.743

EpiControl AF: 0.744

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Benign	0.00086	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.0095	N
LIST_S2	Benign	0.042	T
MetaRNN	Benign	7.0e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.69	N
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.19	N
REVEL	Benign	0.041
Sift	Benign	0.35	T
Sift4G	Benign	0.14	T
Polyphen		0.0	B
Vest4		0.018
MPC		0.073
ClinPred		0.0067	T
GERP RS		4.1
Varity_R		0.020
gMVP		0.053

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

Other links and lift over

dbSNP: rs726817; hg19: chr10-95459817; COSMIC: COSV63272927;