7-101244986-C-T

Variant names:

• chr7-101244986-C-T
• rs1405927224
• NM_016068.3:c.19G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_016068.3(FIS1):​c.19G>A​(p.Glu7Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000682 in 1,613,920 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: FIS1 NM_016068.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.96
• Publications: 0 publications found

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]

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage

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.19G>A	p.Glu7Lys	missense	Exon 1 of 5	NP_057152.2	Q9Y3D6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FIS1	ENST00000223136.5	TSL:1 MANE Select	c.19G>A	p.Glu7Lys	missense	Exon 1 of 5	ENSP00000223136.4	Q9Y3D6
	FIS1	ENST00000474120.5	TSL:1	c.15-4080G>A		intron	N/A	ENSP00000442056.1	F5H8A8
	FIS1	ENST00000473527.5	TSL:1	n.15-847G>A		intron	N/A	ENSP00000444771.1	F5H509

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152272 Hom.: 0 Cov.: 33

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 248862 AF XY: 0.00

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: 0.00000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461648 Hom.: 0 Cov.: 30 AF XY: 0.00000825 AC XY: 6 AN XY: 727148

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000809 AC: 9 AN: 1111916

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152272 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74394

African (AFR) AF: 0.00 AC: 0 AN: 41480

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68050

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.0057	T
MetaRNN	Uncertain	0.43	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.8	L
PhyloP100		5.0
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.15
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.027	D
Polyphen		1.0	D
Vest4		0.55
MutPred		0.38		Gain of methylation at E7 (P = 0.0116)
MVP		0.63
MPC		0.52
ClinPred		0.99	D
GERP RS		5.5
PromoterAI		-0.052	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.42
gMVP		0.40
Mutation Taster		=50/50

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

Other links and lift over

dbSNP: rs1405927224; hg19: chr7-100888267;