rs886037630

Variant names:

• chr9-69053247-ATGTCT-TACACCTTGAGGACA
• rs886037630
• NM_000144.5:c.371_376delATGTCTinsTACACCTTGAGGACA

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM4 PP5

The NM_000144.5(FXN):​c.371_376delATGTCTinsTACACCTTGAGGACA​(p.Asp124_Ser126delinsValHisLeuGluAspThr) variant causes a missense, disruptive inframe insertion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: FXN NM_000144.5 missense, disruptive_inframe_insertion
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.11
• Publications: 0 publications found

Genes affected

FXN (HGNC:3951): (frataxin) This nuclear gene encodes a mitochondrial protein which belongs to the FRATAXIN family. The protein functions in regulating mitochondrial iron transport and respiration. The expansion of intronic trinucleotide repeat GAA from 8-33 repeats to >90 repeats results in Friedreich ataxia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2016]

FXN Gene-Disease associations (from GenCC):

• Friedreich ataxia

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Friedreich ataxia 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• Friedreich ataxia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000285130 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000144.5.
• PP5: Variant 9-69053247-ATGTCT-TACACCTTGAGGACA is Pathogenic according to our data. Variant chr9-69053247-ATGTCT-TACACCTTGAGGACA is described in ClinVar as Pathogenic. ClinVar VariationId is 35514.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000144.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FXN	NM_000144.5	MANE Select	c.371_376delATGTCTinsTACACCTTGAGGACA	p.Asp124_Ser126delinsValHisLeuGluAspThr	missense disruptive_inframe_insertion	N/A	NP_000135.2
	FXN	NM_181425.3		c.371_376delATGTCTinsTACACCTTGAGGACA	p.Asp124_Ser126delinsValHisLeuGluAspThr	missense disruptive_inframe_insertion	N/A	NP_852090.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FXN	ENST00000484259.3	TSL:3 MANE Select	c.371_376delATGTCTinsTACACCTTGAGGACA	p.Asp124_Ser126delinsValHisLeuGluAspThr	missense disruptive_inframe_insertion	N/A	ENSP00000419243.2
	FXN	ENST00000377270.8	TSL:1	c.146_151delATGTCTinsTACACCTTGAGGACA	p.Asp49_Ser51delinsValHisLeuGluAspThr	missense disruptive_inframe_insertion	N/A	ENSP00000366482.4
	FXN	ENST00000498653.5	TSL:1	c.146_151delATGTCTinsTACACCTTGAGGACA	p.Asp49_Ser51delinsValHisLeuGluAspThr	missense disruptive_inframe_insertion	N/A	ENSP00000418015.1

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Friedreich ataxia 1 Pathogenic:1

Nov 01, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.1
Mutation Taster		=1/199	disease causing

Splicing

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

Other links and lift over

dbSNP: rs886037630; hg19: chr9-71668163;