chr10-93684062-T-G

Variant names:

• chr10-93684062-T-G
• rs771208599
• NM_145246.5:c.662A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_145246.5(FRA10AC1):​c.662A>C​(p.His221Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. H221R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FRA10AC1 NM_145246.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.22
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRA10AC1	NM_145246.5	c.662A>C	p.His221Pro	missense_variant	Exon 10 of 14	ENST00000359204.5	NP_660289.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRA10AC1	ENST00000359204.5	c.662A>C	p.His221Pro	missense_variant	Exon 10 of 14	1	NM_145246.5	ENSP00000360488.3
FRA10AC1	ENST00000472153.1	n.255A>C		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250386 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.63	D
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		5.2
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-7.6	D
REVEL	Benign	0.24
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.048	D
Polyphen		0.98	D
Vest4		0.59
MutPred		0.46		Gain of glycosylation at H221 (P = 0.0474);
MVP		0.52
MPC		0.38
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.83
gMVP		0.75
Mutation Taster		=40/60	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs771208599; hg19: chr10-95443819;