rs767135118

Variant names:

• chr9-69035879-T-C
• rs767135118
• NM_000144.5:c.97T>C

Your query was ambiguous. Multiple possible variants found:

• chr9-69035879-T-C
• chr9-69035879-T-G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_000144.5(FXN):​c.97T>C​(p.Leu33Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000758 in 1,319,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: FXN NM_000144.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.09
• 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: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 9-69035879-T-C is Benign according to our data. Variant chr9-69035879-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 518531.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.09 with no splicing effect.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FXN	NM_000144.5	MANE Select	c.97T>C	p.Leu33Leu	synonymous	Exon 1 of 5	NP_000135.2
	FXN	NM_181425.3		c.97T>C	p.Leu33Leu	synonymous	Exon 1 of 5	NP_852090.1	Q16595-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FXN	ENST00000484259.3	TSL:3 MANE Select	c.97T>C	p.Leu33Leu	synonymous	Exon 1 of 5	ENSP00000419243.2	Q16595-1
	ENSG00000285130	ENST00000642889.1		c.97T>C	p.Leu33Leu	synonymous	Exon 1 of 25	ENSP00000493780.1	A0A2R8YDH4
	ENSG00000285130	ENST00000646862.1		c.97T>C	p.Leu33Leu	synonymous	Exon 1 of 6	ENSP00000494599.1	A0A2R8Y577

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.58e-7 AC: 1 AN: 1319984 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 651142

African (AFR) AF: 0.0000380 AC: 1 AN: 26332

American (AMR) AF: 0.00 AC: 0 AN: 30636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22828

East Asian (EAS) AF: 0.00 AC: 0 AN: 29540

South Asian (SAS) AF: 0.00 AC: 0 AN: 74890

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29936

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3828

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1047634

Other (OTH) AF: 0.00 AC: 0 AN: 54360

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.0
DANN	Benign	0.58
PhyloP100		-2.1
PromoterAI		0.029	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs767135118; hg19: chr9-71650795;