dbSNP rs9504370: FARS2:c.-22+10T>C (chr6-5261368-T-C) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_001374878.1(FARS2):c.-45T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.357 in 151,954 control chromosomes in the GnomAD database, including 11,730 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.36 ( 11730 hom., cov: 33)

Exomes 𝑓: 0.18 ( 8 hom. )

Failed GnomAD Quality Control

Consequence

FARS2
NM_001374878.1 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.76

Publications

15 publications found

Variant links:

Genes affected

FARS2 (HGNC:21062): (phenylalanyl-tRNA synthetase 2, mitochondrial) This gene encodes a protein that transfers phenylalanine to its cognate tRNA. This protein localizes to the mitochondrion and plays a role in mitochondrial protein translation. Mutations in this gene can cause combined oxidative phosphorylation deficiency 14 (Alpers encephalopathy). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

FARS2 Gene-Disease associations (from GenCC):

metabolic disease
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
combined oxidative phosphorylation defect type 14
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
hereditary spastic paraplegia 77
Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
Leigh syndrome
Inheritance: AR Classification: MODERATE Submitted by: ClinGen

FARS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.95).

BP6

Variant 6-5261368-T-C is Benign according to our data. Variant chr6-5261368-T-C is described in ClinVar as Benign. ClinVar VariationId is 1250689.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.606 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001374878.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FARS2	NM_001374878.1		c.-45T>C	5_prime_UTR	Exon 1 of 7	NP_001361807.1	O95363
FARS2	NM_001318872.2		c.-22+10T>C	intron	N/A	NP_001305801.1	O95363
FARS2	NM_006567.5	MANE Select	c.-314T>C	upstream_gene	N/A	NP_006558.1	O95363

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FARS2	ENST00000324331.10	TSL:1	c.-22+10T>C	intron	N/A	ENSP00000316335.5	O95363
FARS2	ENST00000897566.1		c.-836T>C	5_prime_UTR	Exon 1 of 8	ENSP00000567625.1
FARS2	ENST00000897567.1		c.-45T>C	5_prime_UTR	Exon 1 of 7	ENSP00000567626.1

Frequencies

GnomAD3 genomes

AF:

0.357

AC:

54205

AN:

151836

Hom.:

11697

Cov.:

show subpopulations

Gnomad AFR

AF:

0.612

Gnomad AMI

AF:

0.155

Gnomad AMR

AF:

0.356

Gnomad ASJ

AF:

0.254

Gnomad EAS

AF:

0.258

Gnomad SAS

AF:

0.165

Gnomad FIN

AF:

0.216

Gnomad MID

AF:

0.357

Gnomad NFE

AF:

0.254

Gnomad OTH

AF:

0.353

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.176

AC:

AN:

484

Hom.:

Cov.:

AF XY:

0.176

AC XY:

AN XY:

358

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AF:

0.500

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.125

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.132

AC:

AN:

174

European-Finnish (FIN)

AF:

0.210

AC:

AN:

Middle Eastern (MID)

AF:

0.500

AC:

AN:

European-Non Finnish (NFE)

AF:

0.203

AC:

AN:

212

Other (OTH)

AF:

0.143

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.532

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.357

AC:

54295

AN:

151954

Hom.:

11730

Cov.:

AF XY:

0.351

AC XY:

26072

AN XY:

74292

show subpopulations

African (AFR)

AF:

0.612

AC:

25351

AN:

41412

American (AMR)

AF:

0.356

AC:

5443

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.254

AC:

880

AN:

3466

East Asian (EAS)

AF:

0.259

AC:

1332

AN:

5150

South Asian (SAS)

AF:

0.164

AC:

791

AN:

4820

European-Finnish (FIN)

AF:

0.216

AC:

2289

AN:

10582

Middle Eastern (MID)

AF:

0.370

AC:

108

AN:

292

European-Non Finnish (NFE)

AF:

0.254

AC:

17222

AN:

67924

Other (OTH)

AF:

0.350

AC:

738

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1655

3310

4966

6621

8276

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

484

968

1452

1936

2420

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.327

Hom.:

13587

Bravo

AF:

0.382

Asia WGS

AF:

0.244

AC:

851

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

4.9

(source)

DANN

Benign

0.69

PhyloP100

-1.8

PromoterAI

-0.016

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over