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

Variant summary

Our verdict is Benign. Variant got -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

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 made for transcript

Verdict is Benign. Variant got -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 id 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FIS1	NM_016068.3 link	c.411G>A	p.Ala137Ala	synonymous_variant	Exon 5 of 5	ENST00000223136.5	NP_057152.2	Q9Y3D6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FIS1	ENST00000223136.5 link	c.411G>A	p.Ala137Ala	synonymous_variant	Exon 5 of 5	1	NM_016068.3	ENSP00000223136.4		Q9Y3D6

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

GnomAD3 exomes

AF:

0.00592

AC:

1407

AN:

237616

Hom.:

AF XY:

0.00613

AC XY:

794

AN XY:

129510

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 SAS exome

AF:

0.00177

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

Gnomad4 AFR exome

AF:

0.00153

Gnomad4 AMR exome

AF:

0.00145

Gnomad4 ASJ exome

AF:

0.000771

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00215

Gnomad4 FIN exome

AF:

0.0106

Gnomad4 NFE exome

AF:

0.00953

Gnomad4 OTH exome

AF:

0.00612

GnomAD4 genome

AF:

0.00579

AC:

881

AN:

152278

Hom.:

Cov.:

AF XY:

0.00608

AC XY:

453

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.00202

Gnomad4 AMR

AF:

0.00170

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00249

Gnomad4 FIN

AF:

0.0154

Gnomad4 NFE

AF:

0.00860

Gnomad4 OTH

AF:

0.00380

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

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FIS1: BP4, BP7, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.32

CADD

Benign

0.25

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

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over