Genetic Variant FIS1:p.Ala137Ala (chr7-101239854-C-T) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBP7BS2

The NM_016068.3(FIS1):c.411G>A(p.Ala137Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0079 in 1,608,854 control chromosomes in the GnomAD database, including 76 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0058 ( 6 hom., cov: 33)

Exomes 𝑓: 0.0081 ( 70 hom. )

Consequence

FIS1
NM_016068.3 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -3.81

Publications

2 publications found

Variant links:

Genes affected

FIS1 (HGNC:21689): (fission, mitochondrial 1) Enables identical protein binding activity. Involved in several processes, including calcium-mediated signaling using intracellular calcium source; cellular calcium ion homeostasis; and mitochondrion organization. Acts upstream of or within mitochondrion morphogenesis. Located in mitochondrion and peroxisome. Is integral component of mitochondrial outer membrane and integral component of peroxisomal membrane. Part of protein-containing complex. Biomarker of Alzheimer's disease. [provided by Alliance of Genome Resources, Apr 2022]

FIS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008183837).

BP6

Variant 7-101239854-C-T is Benign according to our data. Variant chr7-101239854-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2657857.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-3.81 with no splicing effect.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016068.3. 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
	FIS1	NM_016068.3	MANE Select	c.411G>A	p.Ala137Ala	synonymous	Exon 5 of 5	NP_057152.2	Q9Y3D6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FIS1	ENST00000223136.5	TSL:1 MANE Select	c.411G>A	p.Ala137Ala	synonymous	Exon 5 of 5	ENSP00000223136.4	Q9Y3D6
FIS1	ENST00000474120.5	TSL:1	c.*67G>A		3_prime_UTR	Exon 4 of 4	ENSP00000442056.1	F5H8A8
FIS1	ENST00000473527.5	TSL:1	n.*137G>A		non_coding_transcript_exon	Exon 5 of 5	ENSP00000444771.1	F5H509

Frequencies

GnomAD3 genomes

AF:

0.00579

AC:

881

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00203

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00170

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00248

Gnomad FIN

AF:

0.0154

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00860

Gnomad OTH

AF:

0.00384

GnomAD2 exomes

AF:

0.00592

AC:

1407

AN:

237616

AF XY:

0.00613

show subpopulations

Gnomad AFR exome

AF:

0.00155

Gnomad AMR exome

AF:

0.00131

Gnomad ASJ exome

AF:

0.000613

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0104

Gnomad NFE exome

AF:

0.00976

Gnomad OTH exome

AF:

0.00467

GnomAD4 exome

AF:

0.00813

AC:

11836

AN:

1456576

Hom.:

Cov.:

AF XY:

0.00800

AC XY:

5790

AN XY:

724136

show subpopulations

African (AFR)

AF:

0.00153

AC:

AN:

33382

American (AMR)

AF:

0.00145

AC:

AN:

44070

Ashkenazi Jewish (ASJ)

AF:

0.000771

AC:

AN:

25954

East Asian (EAS)

AF:

0.00

AC:

AN:

39504

South Asian (SAS)

AF:

0.00215

AC:

183

AN:

85128

European-Finnish (FIN)

AF:

0.0106

AC:

558

AN:

52864

Middle Eastern (MID)

AF:

0.00226

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00953

AC:

10579

AN:

1109786

Other (OTH)

AF:

0.00612

AC:

368

AN:

60124

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

629

1257

1886

2514

3143

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

382

764

1146

1528

1910

<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:

0.00579

AC:

881

AN:

152278

Hom.:

Cov.:

AF XY:

0.00608

AC XY:

453

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.00202

AC:

AN:

41554

American (AMR)

AF:

0.00170

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5174

South Asian (SAS)

AF:

0.00249

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0154

AC:

163

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00860

AC:

585

AN:

68020

Other (OTH)

AF:

0.00380

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

126

168

210

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00661

Hom.:

Bravo

AF:

0.00464

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.00727

AC:

ESP6500AA

AF:

0.00148

AC:

ESP6500EA

AF:

0.00733

AC:

ExAC

AF:

0.00558

AC:

674

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely 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

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.32

CADD

Benign

0.25

(source)

DANN

Benign

0.97

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.034

LIST_S2

Benign

0.36

MetaRNN

Benign

0.0082

MetaSVM

Benign

-0.63

PhyloP100

-3.8

PROVEAN

Pathogenic

-8.0

REVEL

Benign

0.056

MutPred

0.17

Gain of methylation at G92 (P = 0.004)

MVP

0.54

ClinPred

0.076

GERP RS

-5.6

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

Mutation Taster

=98/2

polymorphism

(source)

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

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