Genetic Variant FIS1:p.Lys149Gln (chr7-101239820-T-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM1

The NM_016068.3(FIS1):c.445A>C(p.Lys149Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000651 in 1,596,442 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000062 ( 0 hom. )

Consequence

FIS1
NM_016068.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.14

Publications

1 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM1

In a mutagenesis_site Protein localizes to both mitochondrion and endoplasmic reticulum. Protein localizes to endoplasmic reticulum only; when associated with A-151. (size 0) in uniprot entity FIS1_HUMAN

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.445A>C	p.Lys149Gln	missense	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.445A>C	p.Lys149Gln	missense	Exon 5 of 5	ENSP00000223136.4	Q9Y3D6
FIS1	ENST00000474120.5	TSL:1	c.*101A>C		3_prime_UTR	Exon 4 of 4	ENSP00000442056.1	F5H8A8
FIS1	ENST00000473527.5	TSL:1	n.*171A>C		non_coding_transcript_exon	Exon 5 of 5	ENSP00000444771.1	F5H509

Frequencies

GnomAD3 genomes

AF:

0.0000987

AC:

AN:

152008

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000640

AC:

AN:

218830

AF XY:

0.0000420

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000144

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000616

AC:

AN:

1444434

Hom.:

Cov.:

AF XY:

0.0000642

AC XY:

AN XY:

717034

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33158

American (AMR)

AF:

0.00

AC:

AN:

42358

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25698

East Asian (EAS)

AF:

0.00

AC:

AN:

38870

South Asian (SAS)

AF:

0.00

AC:

AN:

83550

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51926

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

0.0000743

AC:

AN:

1103434

Other (OTH)

AF:

0.000117

AC:

AN:

59702

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.0000987

AC:

AN:

152008

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74238

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41376

American (AMR)

AF:

0.00

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000221

AC:

AN:

67986

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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

Alfa

AF:

0.0000988

Hom.:

Bravo

AF:

0.000102

ExAC

AF:

0.0000166

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.30

CADD

Pathogenic

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.17

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.81

M_CAP

Pathogenic

0.35

MetaRNN

Uncertain

0.44

MetaSVM

Uncertain

-0.17

MutationAssessor

Pathogenic

2.9

PhyloP100

6.1

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.16

Sift

Uncertain

0.026

Sift4G

Uncertain

0.037

Polyphen

0.012

Vest4

0.55

MVP

0.69

MPC

0.46

ClinPred

0.50

GERP RS

3.6

Varity_R

0.42

gMVP

0.83

Mutation Taster

=82/18

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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