rs886037630

Positions:

• chr9-69053246-GATGTCT-GTACACCTTGAGGACA

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 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

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]

ENSG00000285130 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a mutagenesis_site Drasticly reduces interaction with the core iron-sulfur cluster assembly complex. Does not affect mitochondrial localization. Does not affect proteolytic processing. (size 0) in uniprot entity FRDA_HUMAN
• 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 id is 35514.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FXN	NM_000144.5	c.371_376delATGTCTinsTACACCTTGAGGACA	p.Asp124_Ser126delinsValHisLeuGluAspThr	missense_variant, disruptive_inframe_insertion		ENST00000484259.3	NP_000135.2
FXN	NM_181425.3	c.371_376delATGTCTinsTACACCTTGAGGACA	p.Asp124_Ser126delinsValHisLeuGluAspThr	missense_variant, disruptive_inframe_insertion			NP_852090.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FXN	ENST00000484259.3	c.371_376delATGTCTinsTACACCTTGAGGACA	p.Asp124_Ser126delinsValHisLeuGluAspThr	missense_variant, disruptive_inframe_insertion		3	NM_000144.5	ENSP00000419243.2
ENSG00000285130	ENST00000642889.1	c.165+17300_165+17305delATGTCTinsTACACCTTGAGGACA		intron_variant				ENSP00000493780.1

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2011

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs886037630; hg19: chr9-71668163;