10-93700060-C-T

Variant names:

• chr10-93700060-C-T
• rs726817
• NM_145246.5:c.47G>A

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 37 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: Benign. The variant received -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 rank	MANE	Protein	UniProt
FRA10AC1	NM_145246.5	c.47G>A	p.Arg16His	missense_variant	Exon 2 of 14	ENST00000359204.5	NP_660289.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRA10AC1	ENST00000359204.5	c.47G>A	p.Arg16His	missense_variant	Exon 2 of 14	1	NM_145246.5	ENSP00000360488.3

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

GnomAD2 exomes AF: 0.701 AC: 173370 AN: 247310 AF XY: 0.704

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 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

African (AFR) AF: 0.494 AC: 16268 AN: 32944

American (AMR) AF: 0.687 AC: 30119 AN: 43834

Ashkenazi Jewish (ASJ) AF: 0.813 AC: 21098 AN: 25964

East Asian (EAS) AF: 0.705 AC: 27807 AN: 39470

South Asian (SAS) AF: 0.640 AC: 54505 AN: 85098

European-Finnish (FIN) AF: 0.709 AC: 37042 AN: 52230

Middle Eastern (MID) AF: 0.745 AC: 4274 AN: 5734

European-Non Finnish (NFE) AF: 0.734 AC: 804451 AN: 1096110

Other (OTH) AF: 0.719 AC: 42895 AN: 59686

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

African (AFR) AF: 0.505 AC: 20922 AN: 41430

American (AMR) AF: 0.684 AC: 10455 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.816 AC: 2829 AN: 3468

East Asian (EAS) AF: 0.699 AC: 3614 AN: 5168

South Asian (SAS) AF: 0.627 AC: 3020 AN: 4816

European-Finnish (FIN) AF: 0.711 AC: 7526 AN: 10580

Middle Eastern (MID) AF: 0.786 AC: 231 AN: 294

European-Non Finnish (NFE) AF: 0.734 AC: 49922 AN: 67982

Other (OTH) AF: 0.683 AC: 1443 AN: 2114

Alfa AF: 0.714 Hom.: 129610

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
PhyloP100		0.33
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
Mutation Taster		=99/1	polymorphism (auto)

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