chr7-101247300-A-AAAAAAAAATATAT

Variant names:

• chr7-101247300-A-AAAAAAAAATATAT
• rs762133451
• ENST00000474120.5:c.14+4594_14+4595insATATATTTTTTTT

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The ENST00000474120.5(FIS1):​c.14+4594_14+4595insATATATTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 141,914 control chromosomes in the GnomAD database, including 16 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: 𝑓 0.012 (16 hom., cov: 27)
• Consequence: FIS1 ENST00000474120.5 intron
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: -2.26
• 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: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0122 (1736/141914) while in subpopulation NFE AF = 0.0205 (1354/65956). AF 95% confidence interval is 0.0196. There are 16 homozygotes in GnomAd4. There are 786 alleles in the male GnomAd4 subpopulation. Median coverage is 27. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 16 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000474120.5. 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
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FIS1	ENST00000474120.5	TSL:1	c.14+4594_14+4595insATATATTTTTTTT		intron	N/A	ENSP00000442056.1	F5H8A8
	FIS1	ENST00000473527.5	TSL:1	n.15-3162_15-3161insATATATTTTTTTT		intron	N/A	ENSP00000444771.1	F5H509
	FIS1	ENST00000435848.1	TSL:5	c.15-3162_15-3161insATATATTTTTTTT		intron	N/A	ENSP00000413500.1	C9JXH1

Frequencies

GnomAD3 genomes AF: 0.0122 AC: 1736 AN: 141900 Hom.: 16 Cov.: 27

Gnomad AFR AF: 0.00349

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00721

Gnomad ASJ AF: 0.0114

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0110

Gnomad FIN AF: 0.00489

Gnomad MID AF: 0.0137

Gnomad NFE AF: 0.0205

Gnomad OTH AF: 0.00878

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0122 AC: 1736 AN: 141914 Hom.: 16 Cov.: 27 AF XY: 0.0115 AC XY: 786 AN XY: 68610

African (AFR) AF: 0.00348 AC: 132 AN: 37932

American (AMR) AF: 0.00720 AC: 101 AN: 14024

Ashkenazi Jewish (ASJ) AF: 0.0114 AC: 39 AN: 3410

East Asian (EAS) AF: 0.00 AC: 0 AN: 4990

South Asian (SAS) AF: 0.0111 AC: 50 AN: 4516

European-Finnish (FIN) AF: 0.00489 AC: 39 AN: 7982

Middle Eastern (MID) AF: 0.0150 AC: 4 AN: 266

European-Non Finnish (NFE) AF: 0.0205 AC: 1354 AN: 65956

Other (OTH) AF: 0.00873 AC: 17 AN: 1948

Alfa AF: 0.00455 Hom.: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-2.3
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs762133451; hg19: chr7-100890581;