dbSNP rs17139985: FARS2:c.-22+12T>C (chr6-5261370-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.-43T>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 152,014 control chromosomes in the GnomAD database, including 11,732 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.36 ( 11732 hom., cov: 33)

Exomes 𝑓: 0.19 ( 9 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: -0.445

Publications

5 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=-0.88).

BP6

Variant 6-5261370-T-C is Benign according to our data. Variant chr6-5261370-T-C is described in ClinVar as Benign. ClinVar VariationId is 1243161.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.-43T>C	5_prime_UTR	Exon 1 of 7	NP_001361807.1	O95363
FARS2	NM_001318872.2		c.-22+12T>C	intron	N/A	NP_001305801.1	O95363
FARS2	NM_006567.5	MANE Select	c.-312T>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+12T>C	intron	N/A	ENSP00000316335.5	O95363
FARS2	ENST00000897566.1		c.-834T>C	5_prime_UTR	Exon 1 of 8	ENSP00000567625.1
FARS2	ENST00000897567.1		c.-43T>C	5_prime_UTR	Exon 1 of 7	ENSP00000567626.1

Frequencies

GnomAD3 genomes

AF:

0.357

AC:

54214

AN:

151896

Hom.:

11699

Cov.:

show subpopulations

Gnomad AFR

AF:

0.611

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:

0.354

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.186

AC:

AN:

468

Hom.:

Cov.:

AF XY:

0.179

AC XY:

AN XY:

346

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:

0.141

AC:

AN:

156

European-Finnish (FIN)

AF:

0.258

AC:

AN:

Middle Eastern (MID)

AF:

0.250

AC:

AN:

European-Non Finnish (NFE)

AF:

0.209

AC:

AN:

206

Other (OTH)

AF:

0.0833

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:

54304

AN:

152014

Hom.:

11732

Cov.:

AF XY:

0.351

AC XY:

26077

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.612

AC:

25354

AN:

41426

American (AMR)

AF:

0.356

AC:

5442

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.254

AC:

880

AN:

3466

East Asian (EAS)

AF:

0.258

AC:

1333

AN:

5158

South Asian (SAS)

AF:

0.164

AC:

791

AN:

4820

European-Finnish (FIN)

AF:

0.216

AC:

2287

AN:

10592

Middle Eastern (MID)

AF:

0.370

AC:

108

AN:

292

European-Non Finnish (NFE)

AF:

0.254

AC:

17229

AN:

67952

Other (OTH)

AF:

0.351

AC:

739

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1670

3341

5011

6682

8352

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:

0.313

Hom.:

1088

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

-0.88

CADD

Benign

5.4

(source)

DANN

Benign

0.69

PhyloP100

-0.45

PromoterAI

0.016

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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