chr10-93681495-T-G

Variant names:

• chr10-93681495-T-G
• rs7914441
• NM_145246.5:c.772A>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_145246.5(FRA10AC1):​c.772A>C​(p.Lys258Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00015 in 1,571,746 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00087 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000073 (0 hom.)
• Consequence: FRA10AC1 NM_145246.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.521
• Publications: 1 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0051822066).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000874 (133/152256) while in subpopulation AFR AF = 0.00308 (128/41578). AF 95% confidence interval is 0.00264. There are 0 homozygotes in GnomAd4. There are 59 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.772A>C	p.Lys258Gln	missense	Exon 11 of 14	NP_660289.2
	FRA10AC1	NM_001347712.2		c.772A>C	p.Lys258Gln	missense	Exon 11 of 14	NP_001334641.1	Q70Z53-1
	FRA10AC1	NM_001347713.2		c.772A>C	p.Lys258Gln	missense	Exon 12 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.772A>C	p.Lys258Gln	missense	Exon 11 of 14	ENSP00000360488.3	Q70Z53-1
	FRA10AC1	ENST00000959343.1		c.775A>C	p.Lys259Gln	missense	Exon 11 of 14	ENSP00000629402.1
	FRA10AC1	ENST00000905754.1		c.772A>C	p.Lys258Gln	missense	Exon 11 of 14	ENSP00000575813.1

Frequencies

GnomAD3 genomes AF: 0.000874 AC: 133 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00309

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000231 AC: 51 AN: 220796 AF XY: 0.000225

Gnomad AFR exome AF: 0.00313

Gnomad AMR exome AF: 0.000155

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: 0.000191

GnomAD4 exome AF: 0.0000726 AC: 103 AN: 1419490 Hom.: 0 Cov.: 27 AF XY: 0.0000707 AC XY: 50 AN XY: 706858

African (AFR) AF: 0.00275 AC: 84 AN: 30570

American (AMR) AF: 0.000140 AC: 5 AN: 35720

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 38332

South Asian (SAS) AF: 0.0000127 AC: 1 AN: 78942

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5650

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1093856

Other (OTH) AF: 0.000221 AC: 13 AN: 58718

GnomAD4 genome AF: 0.000874 AC: 133 AN: 152256 Hom.: 0 Cov.: 32 AF XY: 0.000793 AC XY: 59 AN XY: 74440

African (AFR) AF: 0.00308 AC: 128 AN: 41578

American (AMR) AF: 0.000327 AC: 5 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67978

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00246 Hom.: 0

Bravo AF: 0.000873

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000239 AC: 29

Asia WGS AF: 0.000289 AC: 1 AN: 3472

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	15
DANN	Benign	0.90
DEOGEN2	Benign	0.0018	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.52
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.039
Sift	Benign	0.42	T
Sift4G	Benign	0.39	T
Polyphen		0.011	B
Vest4		0.13
MVP		0.27
MPC		0.064
ClinPred		0.0044	T
GERP RS		4.0
Varity_R		0.071
gMVP		0.25
Mutation Taster		=87/13	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: rs7914441; hg19: chr10-95441252;