rs1427003828

Variant names:

• chr10-93687418-ACTT-A
• rs1427003828
• NM_145246.5:c.494_496delAAG

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2 PM4_Supporting PP5_Very_Strong

The NM_145246.5(FRA10AC1):​c.494_496delAAG​(p.Glu165del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00000264 in 1,515,708 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: FRA10AC1 NM_145246.5 disruptive_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.15
• 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: Pathogenic. The variant received 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_145246.5. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 10-93687418-ACTT-A is Pathogenic according to our data. Variant chr10-93687418-ACTT-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1722515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.494_496delAAG	p.Glu165del	disruptive_inframe_deletion	Exon 8 of 14	NP_660289.2
	FRA10AC1	NM_001347712.2		c.494_496delAAG	p.Glu165del	disruptive_inframe_deletion	Exon 8 of 14	NP_001334641.1	Q70Z53-1
	FRA10AC1	NM_001347713.2		c.494_496delAAG	p.Glu165del	disruptive_inframe_deletion	Exon 9 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.494_496delAAG	p.Glu165del	disruptive_inframe_deletion	Exon 8 of 14	ENSP00000360488.3	Q70Z53-1
	FRA10AC1	ENST00000959343.1		c.497_499delAAG	p.Glu166del	disruptive_inframe_deletion	Exon 8 of 14	ENSP00000629402.1
	FRA10AC1	ENST00000905754.1		c.494_496delAAG	p.Glu165del	disruptive_inframe_deletion	Exon 8 of 14	ENSP00000575813.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 151980 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000479

GnomAD4 exome AF: 7.33e-7 AC: 1 AN: 1363728 Hom.: 0 AF XY: 0.00000147 AC XY: 1 AN XY: 678022

African (AFR) AF: 0.00 AC: 0 AN: 29946

American (AMR) AF: 0.00 AC: 0 AN: 34808

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23484

East Asian (EAS) AF: 0.00 AC: 0 AN: 37640

South Asian (SAS) AF: 0.0000128 AC: 1 AN: 78076

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50122

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5422

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1048306

Other (OTH) AF: 0.00 AC: 0 AN: 55924

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 151980 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74230

African (AFR) AF: 0.0000483 AC: 2 AN: 41436

American (AMR) AF: 0.00 AC: 0 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67878

Other (OTH) AF: 0.000479 AC: 1 AN: 2088

Alfa AF: 0.0000843 Hom.: 0

Bravo AF: 0.0000302

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Neurodevelopmental disorder with growth retardation, dysmorphic facies, and corpus callosum abnormalities (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.1
Mutation Taster		=5/95	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.32		Position offset: -14

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1427003828; hg19: chr10-95447175;