rs750274023

Variant names:

• chr9-69046440-A-C
• NM_000144.5:c.221A>C

Your query was ambiguous. Multiple possible variants found:

• chr9-69046440-A-C
• chr9-69046440-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000144.5(FXN):​c.221A>C​(p.Tyr74Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: FXN NM_000144.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0680

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 Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a chain Frataxin(56-210) (size 154) in uniprot entity FRDA_HUMAN there are 8 pathogenic changes around while only 2 benign (80%) in NM_000144.5
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09696582).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FXN	NM_000144.5	c.221A>C	p.Tyr74Ser	missense_variant	Exon 2 of 5	ENST00000484259.3	NP_000135.2
FXN	NM_181425.3	c.221A>C	p.Tyr74Ser	missense_variant	Exon 2 of 5		NP_852090.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FXN	ENST00000484259.3	c.221A>C	p.Tyr74Ser	missense_variant	Exon 2 of 5	3	NM_000144.5	ENSP00000419243.2
ENSG00000285130	ENST00000642889.1	c.165+10493A>C		intron_variant	Intron 1 of 24			ENSP00000493780.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461814 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727202

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	13
DANN	Benign	0.33
DEOGEN2	Benign	0.31	T;.;.;T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.47	.;T;T;T;T
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.097	T;T;T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.6	L;L;L;L;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.0	.;N;N;.;.
REVEL	Benign	0.24
Sift	Benign	0.33	.;T;T;.;.
Sift4G	Benign	0.37	.;T;T;.;.
Polyphen		0.17	B;B;.;B;.
Vest4		0.082, 0.090
MutPred		0.60		Gain of disorder (P = 0.0026);Gain of disorder (P = 0.0026);Gain of disorder (P = 0.0026);Gain of disorder (P = 0.0026);Gain of disorder (P = 0.0026);
MVP		0.49
ClinPred		0.11	T
GERP RS		-5.3
Varity_R		0.22
gMVP		0.32

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-71661356;